Pyrazole compounds that modulate HSP90 activity

ABSTRACT

Compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I) and methods of inhibiting Hsp90 in a cell, treating or preventing a proliferation disorder in a mammal and treating cancer in a mammal comprising administering a compound of formula (I) to a patient or a cell. 
                         
Variable R 5  is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl; a bicyclic 9-member heterocycle optionally substituted at any substitutable nitrogen or carbon atoms; or a substituent R 18 , defined herein. Ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to R 3 . Substituent R 3  is defined herein.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/559,155, filed Sep. 14, 2009, and is a divisional application ofU.S. application Ser. No. 11/502,346, filed Aug. 10, 2006, now U.S. Pat.No. 7,608,635, issued on Oct. 27, 2009, and claims the benefit under 35U.S.C. 119 or 365 of U.S. Provisional Application No. 60/707,836, filedon Aug. 12, 2005. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Although tremendous advances have been made in elucidating the genomicabnormalities that cause malignant cancer cells, currently availablechemotherapy remains unsatisfactory, and the prognosis for the majorityof patients diagnosed with cancer remains dismal. Most chemotherapeuticagents act on a specific molecular target thought to be involved in thedevelopment of the malignant phenotype. However, a complex network ofsignaling pathways regulate cell proliferation, and the majority ofmalignant cancers are facilitated by multiple genetic abnormalities inthese pathway. Therefore, it is unlikely that a therapeutic agent thatacts on one molecular target will be fully effective in curing a patientwho has cancer.

Heat shock proteins (HSPs) are a class of chaperone proteins that areup-regulated in response to elevated temperature and other environmentalstresses, such as ultraviolet light, nutrient deprivation, and oxygendeprivation. HSPs act as chaperones to other cellular proteins (calledclient proteins) and facilitate their proper folding and repair, and aidin the refolding of misfolded client proteins. There are several knownfamilies of HSPs, each having its own set of client proteins. The Hsp90family is one of the most abundant HSP families, accounting for about1-2% of proteins in a cell that is not under stress and increasing toabout 4-6% in a cell under stress. Inhibition of Hsp90 results indegradation of its client proteins via the ubiquitin proteasome pathway.Unlike other chaperone proteins, the client proteins of Hsp90 are mostlyprotein kinases or transcription factors involved in signaltransduction, and a number of its client proteins have been shown to beinvolved in the progression of cancer. Examples of Hsp90 client proteinsthat have been implicated in the progression of cancer are describedbelow.

Her-2 is a transmembrane tyrosine kinase cell surface growth factorreceptor that is expressed in normal epithelial cells. Her2 has anextracellular domain that interacts with extracellular growth factorsand an internal tyrosine kinase portion that transmits the externalgrowth signal to the nucleus of the cell. Her2 is overexpressed in asignificant proportion of malignancies, such as breast cancer, ovariancancer, prostate cancer, and gastric cancers, and is typicallyassociated with a poor prognosis.

Akt kinase is a serine/threonine kinase which is a downstream effectormolecule of phosphoinositide 3-kinase and is involved in protecting thecell from apoptosis. Akt kinase is thought to be involved in theprogression of cancer because it stimulates cell proliferation andsuppresses apoptosis.

Cdk4/cyclin D complexes are involved in phosphorylation ofretinoblastoma protein which is an essential step in progression of acell through the G1 phase of the cell cycle. Disruption of Hsp90activity has been shown to decrease the half life of newly synthesizedCdk4.

Raf-1 is a MAP 3-kinase (MAP3K) which when activated can phosphorylateand activate the serine/threonine specific protein kinases ERK1 andERK2. Activated ERKs play an important role in the control of geneexpression involved in the cell division cycle, apoptosis, celldifferentiation and cell migration.

The transforming protein of Rous sarcoma virus, v-src, is a prototype ofan oncogene family that induces cellular transformation (i.e.,tumorogenesis) by non-regulated kinase activity. Hsp90 has been shown tocomplex with v-scr and inhibit its degradation.

Hsp90 is required to maintain steroid hormone receptors in aconformation capable of binding hormone with high affinity. Inhibitionof the action of Hsp90 therefore is expected to be useful in treatinghormone-associated malignancies such as breast cancer.

p53 is a tumor suppressor protein that causes cell cycle arrest andapoptosis. Mutation of the p53 gene is found in about half of all humancancers making it one of the most common genetic alterations found incancerous cells. In addition, p53 mutation is associated with a poorprognosis. Wild-type p53 has been shown to interact with Hsp90, butmutated p53 forms a more stable association than wild-type p53 as aresult of its misfolded conformations. A stronger interaction with Hsp90protects the mutated protein form normal proteolytic degradation andprolongs its half-life. In a cell that is heterozygous for mutated andwild-type p53, inhibition of the stabilizing effect of Hsp90 causesmutant p53 to be degraded and restores the normal transcriptionalactivity of wild-type p53.

Hif-1α is a hypoxia-inducible transcription factor that is up-regulatedunder low oxygen conditions. Under normal oxygen conditions Hif-1αassociates with Von Hippel-Lindau (VHL) tumor suppressor protein and isdegraded. Low oxygen conditions inhibit this association and allowsHif-1α to accumulate and complex with Hif-1β to form an activetranscription complex that associates with hypoxia-response elements toactivate the transcription of vascular endothelial growth factor (VEGF).Increased Hif-1α is associated with increased metastasis and a poorprognosis.

There are two classes of PKs: protein tyrosine kinases (PTKs), whichcatalyze the phosphorylation of tyrosine kinase residues, and theserine-threonine kinases (STKs), which catalyze the phosphorylation ofserine or threonine residues. Growth factor receptors with PTK activityare known as receptor tyrosine kinases. Receptor tyrosine kinases are afamily of tightly regulated enzymes, and the aberrant activation ofvarious members of the family is one of the hallmarks of cancer. Thereceptor tyrosine kinase family can be divided into subgroups that havesimilar structural organization and sequence similarity within thekinase domain.

Epidermal Growth Factor Receptor (EGFR) is a member of the type 1subgroup of receptor tyrosine kinase family of growth factor receptors,which play critical roles in cellular growth, differentiation, andsurvival. Activation of these receptors typically occurs via specificligand binding which results in hetero- or homodimerization betweenreceptor family members, with subsequent autophosphorylation of thetyrosine kinase domain. Specific ligands which bind to EGFR includeepidermal growth factor (EGF), transforming growth factor α (TGFα),amphiregulin and some viral growth factors. Activation of EGFR triggersa cascade of intracellular signaling pathways involved in both cellularproliferation (the ras/raf/MAP kinase pathway) and survival (the PI3kinase/Akt pathway). Members of this family, including EGFR and HER2,have been directly implicated in cellular transformation.

A number of human malignancies are associated with aberrant oroverexpression of EGFR and/or overexpression of its specific ligands(Gullick, Br. Med. Bull. (1991), 47:87-98; Modijtahedi and Dean, Int. J.Oncol. (1994), 4:277-96; Salomon, et al., Crit. Rev. Oncol. Hematol.(1995); 19:183-232, the entire teachings of each of these references areincorporated herein by reference). Aberrant or overexpression of EGFRhas been associated with an adverse prognosis in a number of humancancers, including head and neck, breast, colon, prostate, lung (e.g.,NSCLC, adenocarcinoma and squamous lung cancer), ovaries,gastrointestinal cancers (gastric, colon, pancreatic), renal cellcancer, bladder cancer, glioma, gynecological carcinomas, and prostatecancer. In some instances, overexpression of tumor EGFR has beencorrelated with both chemoresistance and a poor prognosis (Lei, et al.,Anticancer Res. (1999), 19:221-8; Veale, et al., Br. J. Cancer (1993);68:162-5, the entire teachings of each of these references areincorporated herein by reference).

Gefitinib, a chemotherapeutic agent that inhibits the activity of EGFR,has been found to be highly efficacious in a subset of lung cancerpatients that have mutations in the tyrosine kinase domain of EGFR. Inthe presence of EGF, these mutants displayed two to three times higheractivity than wild type EGFR. In addition, wild type EGFR wasinternalized by the cells and down-regulated after 15 minutes, where asmutant EGFR was internalized more slowly and continued to be activatedfor up to three hours (Lynch, et al., The New England Journal ofMedicine (2006), 350:2129-2139, the entire teachings of which areincorporated herein by reference).

Gliomas are another type of cancer that is characterized byamplification and/or mutation of the EGFR gene. One of the most commonmutations in the EGFR gene is a deletion of exons 2-7 which results in atruncated form of EGFR in which amino acids 6-273 of the extracellulardomain are replaced with a single glycine residue. This mutation iscalled EGFRvIII and is expressed in about half of all glioblastomas.EGFRvIII is unable to bind EGF and TGFα and has constitutive,ligand-independent tyrosine kinase activity. Hsp90 co-purifies withEGFRvIII indicating that Hsp90 complexes with EGFRvIII. Moreover, Hsp90inhibitor geldanamycin, a benzoquinone ansamycin antibiotic, was able todecrease the expression of EGFRvIII indicating that interaction withHsp90 is essential to maintain high expression levels of EGFRvIII(Lavictoire, et al., Journal of Biological Chemistry (2003),278(7):5292-5299, the entire teachings of which are incorporated hereinby reference). These results demonstrate that inhibiting the activity ofHsp90 is an effective strategy for treating cancers that are associatedwith inappropriate EGFR activity.

The members of the type III group of receptor tyrosine kinases includeplatelet-derived growth factor (PDGF) receptors (PDGF receptors alphaand beta), colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms),Fms-like tyrosine kinase (FLT3), and stem cell factor receptor (c-kit).F1LT3 is primarily expressed on immature hematopoietic progenitors andregulates their proliferation and survival.

Hematologic cancers, also known as hematologic or hematopoieticmalignancies, are cancers of the blood or bone marrow; includingleukemia and lymphoma. Acute myelogenous leukemia (AML) is a clonalhematopoietic stem cell leukemia that represents about 90% of all acuteleukemias in adults with an incidence of 3.9 per 100,000 (See e.g.,Lowenberg et al., N. Eng. J. Med. 341: 1051-62 (1999) and LopesdeMenezes, et al, Clin. Cancer Res. (2005), 11(14):5281-5291, the enterteachings of both references are incorporated by reference). Whilechemotherapy can result in complete remissions, the long termdisease-free survival rate for AML is about 14% with about 7,400 deathsfrom AML each year in the United States. Approximately 70% of AML blastsexpress wild type FLT3 and about 25% to about 35% express FLT3 kinasereceptor mutations which result in constitutively active FLT3. Two typesof activating mutations have been identified in AML patients: internaltandem duplications (ITDs) and point mutation in the activating loop ofthe kinase domain. FLT3-ITD mutations in AML patients is indicative of apoor prognosis for survival, and in patients who are in remission,FLT3-ITD mutations are the most significant factor adversely affectingrelapse rate with 64% of patients having the mutation relapsing within 5years (see Current Pharmaceutical Design (2005), 11:3449-3457, theentire teachings of which are incorporated herein by reference). Theprognostic significance of FLT3 mutations in clinical studies suggeststhat FLT3 plays a driving role in AML and may be necessary for thedevelopment and maintenance of the disease.

Mixed Lineage Leukemia (MLL) involve translocations of chromosome 11band q23 (11q23) and occur in approximately 80% of infant hematologicalmalignancies and 10% of adult acute leukemias. Although certain 11q23translocation have been shown to be essential to immortalization ofhematopoietic progenitors in vitro, a secondary genotoxic event isrequired to develop leukemia. There is a strong concordance between FLT3and MLL fusion gene expression, and the most consistently overexpressedgene in MLL is FLT3. Moreover, it has been shown that activated FLT3together with MLL fusion gene expression induces acute leukemia with ashort latency period (see Ono, et al., J. of Clinical Investigation(2005), 115:919-929, the entire teachings of which are incorporated byreference). Therefore, it is believed that FLT3 signally is involved inthe development and maintenance of MLL (see Armstrong, et al., CancerCell (2003), 3:173-183, the entire teachings of which are incorporatedherein by reference).

The FLT3-ITD mutation is also present in about 3% of cases of adultmyelodysplastic syndrome and some cases of acute lymphocytic leukemia(ALL) (Current Pharmaceutical Design (2005), 11:3449-3457).

FLT3 has been shown to be a client protein of Hsp90, and 17AAG, abenzoquinone ansamycin antibiotic that inhibits Hsp90 activity, has beenshown to disrupts the association of F1t3 with Hsp90. The growth ofleukemia cell that express either wild type FLT3 or FLT3-ITD mutationswas found to be inhibited by treatment with 17″ AAG (Yao, et al.,Clinical Cancer Research (2003), 9:4483-4493, the entire teachings ofwhich are incorporated herein by reference).

c-Kit is a membrane type III receptor protein tyrosine kinase whichbinds Stem Cell Factor (SCF) to its extracellular domain. c-Kit hastyrosine kinase activity and is required for normal hematopoiesis.However, mutations in c-kit can result in ligand-independent tyrosinekinase activity, autophosphorylation, and uncontrolled cellproliferation. Aberrant expression and/or activation of c-Kit has beenimplicated in a variety of pathologic states. For example, evidence fora contribution of c-Kit to neoplastic pathology includes its associationwith leukemias and mast cell tumors, small cell lung cancer, testicularcancer, and some cancers of the gastrointestinal tract and centralnervous system. In addition, c-Kit has been implicated in playing a rolein carcinogenesis of the female genital tract sarcomas ofneuroectodermal origin, and Schwann cell neoplasia associated withneurofibromatosis. (Yang et al., J Clin Invest. (2003), 112:1851-1861;Viskochil, J Clin Invest. (2003), 112:1791-1793, the entire teachings ofeach of these reference are incorporated herein by reference). c-Kit hasbeen shown to be a client protein of Hsp90, and Hsp90 inhibitor 17AAG, abenzoquinon ansamycin, has been shown to induce apoptosis in Kasumi-1cells, an acute myeloid leukemia cell line that harbors a mutation inc-kit.

c-Met is a receptor tyrosine kinase that is encoded by the Metprotooncogene and transduces the biological effects of hepatocyte growthfactor (HGF), which is also referred to as scatter factor (SF). Jiang etal., Crit. Rev. Oncol. Hemtol. 29: 209-248 (1999), the entire teachingsof which are incorporated herein by reference. c-Met and HGF areexpressed in numerous tissues, although their expression is normallyconfined predominantly to cells of epithelial and mesenchymal origin,respectively. c-Met and HGF are required for normal mammaliandevelopment and have been shown to be important in cell migration, cellproliferation and survival, morphogenic differentiation, andorganization of 3-dimensional tubular structures (e.g., renal tubularcells, gland formation, etc.). The c-Met receptor has been shown to beexpressed in a number of human cancers. c-Met and its ligand, HGF, havealso been shown to be co-expressed at elevated levels in a variety ofhuman cancers (particularly sarcomas). However, because the receptor andligand are usually expressed by different cell types, c-Met signaling ismost commonly regulated by tumor-stroma (tumor-host) interactions.Furthermore, c-Met gene amplification, mutation, and rearrangement havebeen observed in a subset of human cancers. Families with germinemutations that activate c-Met kinase are prone to multiple kidney tumorsas well as tumors in other tissues. Numerous studies have correlated theexpression of c-Met and/or HGF/SF with the state of disease progressionof different types of cancer (including lung, colon, breast, prostate,liver, pancreas, brain, kidney, ovarian, stomach, skin, and bonecancers). Furthermore, the overexpression of c-Met or HGF have beenshown to correlate with poor prognosis and disease outcome in a numberof major human cancers including lung, liver, gastric, and breast.

BCR-ABL is an ocoprotein with tyrosine kinase activity and has beenassociated with chronic myelogenous leukemia (CML), with a subset ofpatients with acute lymphocytic leukemia (ALL) and with a subset ofpatients with acute myelogenous leukemia (AML). In fact, the BCR-ABLoncogene has been found in at least 90-95% of patients with CML, 20% ofadults with ALL, 5% of children with ALL, and in about 2% of adults withAML. The BCR-ABL oncoprotein is generated by the transloction of genesequences from the c-ABL protein tyrosine kinase on chromosome 9 intothe BCR sequences on chromosome 22, producing the Philadelphiachromosome. The BCR-ABL gene has been shown to produce at least threealternative chimeric proteins, p230 Bcr-Abl, p210 Bcr-Abl, and p190Bcr-Abl which have unregulated tyrosine kinase activity. The p210Bcr-Abl fusion protein is most often associated with CML, while the p190Bcr-Abl fusion protein is most often associated with ALL. Bcr-Abl hasalso been associated with a variety of additional hematologicalmalignancies including granulocytic hyperplasia, myelomonocyticleukemia, lymphomas and erythroid leukemia.

Studies have shown that lowering the expression or activity of Bcr-Ablis effective in treating Bcr-Abl-positive leukemias. For example, agentssuch as As₂O₃ which lower Bcr-Abl expression have been shown to behighly effective against Bcr-Abl leukemias. In addition, inhibition ofBcr-Abl tyrosine kinase activity by Imatinib (also known as STI571 andGleevic) induces differentiation and apoptosis and causes eradication ofBcr-Abl positive leukemia cells both in vivo and in vitro. In patientswith CML in the chronic phase, as well as in a blast crisis, treatmentwith Imatinib typically will induce remission. However, in many cases,particularly in those patients who were in a blast crisis beforeremission, the remission is not durable because the Bcr-Abl fusionprotein develops mutations that cause it to be resistance to Imatinib.(See Nimmanapalli, et al., Cancer Research (2001), 61:1799-1804; andGorre, et al., Blood (2002), 100:3041-3044, the entire teachings of eachof these references are incorporated herein by reference).

Bcr-Abl fusion proteins exist as complexes with Hsp90 and are rapidlydegraded when the action of Hsp90 is inhibited. It has been shown thatgeldanamycin, a benzoquinone ansamycin antibiotic that disrupts theassociation of Bcr-Abl with Hsp90, results in proteasomal degradation ofBcr-Abl and induces apoptosis in Bcr-Abl leukemia cells.

Hsp90 has been shown by mutational analysis to be necessary for thesurvival of normal eukaryotic cells. However, Hsp90 is over expressed inmany tumor types indicating that it may play a significant role in thesurvival of cancer cells and that cancer cells may be more sensitive toinhibition of Hsp90 than normal cells. For example, cancer cellstypically have a large number of mutated and overexpressed oncoproteinsthat are dependent on Hsp90 for folding. In addition, because theenvironment of a tumor is typically hostile due to hypoxia, nutrientdeprivation, acidosis, etc., tumor cells may be especially dependent onHsp90 for survival. Moreover, inhibition of Hsp90 causes simultaneousinhibition of a number of oncoproteins, as well as hormone receptors andtranscription factors making it an attractive target for an anti-canceragent. In fact, benzoquinone ansamycins, a family of natural productsthat inhibit Hsp90, has shown evidence of therapeutic activity inclinical trials.

Although promising, benzoquinone ansamycins, and their derivatives,suffer from a number of limitations. For example, they have low oralbioavailability, and their limited solubility makes them difficult toformula. In addition, they are metabolized by polymorphic cytochromeP450 CYP3A4 and are a substrate for P-glycoprotein export pump involvedin the development of multidrug resistance. Therefore, a need exist fornew therapeutics that improve the prognosis of cancer patients and thatreduces or overcomes the limitations of currently used anti-canceragents.

SUMMARY OF THE INVENTION

The present invention is novel compounds, pharmaceutical compositionscomprising same and methods of treatment of proliferative disorders,such as cancer, comprising administering the compounds of the presentinvention. The compounds of the present invention inhibit the activityof Hsp90. It has been shown that the compounds of the present inventioninhibit Hsp90 protein (Example 1) and thereby lead to degradation ofHsp90 client proteins such as Her2 gene product (Example 2).

In one embodiment, the present invention is an Hsp90 inhibitorrepresented by structural formula (Ia):

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, ora prodrug thereof. In formula (Ia):

ring A is an aryl or a heteroaryl, wherein the aryl or the heteroarylare optionally further substituted with one or more substituents inaddition to R₃;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₅ is an optionally substituted heteroaryl or an optionally substituted8 to 14-membered aryl;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In another embodiment of the present invention, the Hsp90 inhibitor isrepresented by structural formula (Ib):

In formula (Ib), R₂ is an optionally substituted phenyl group.Preferably, R₂ is substituted with one or more group represented by R₃₀,wherein R₃₀, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. The remainder of the variables in structural formula (Ib)have values defined above with reference to structural formula (Ia).

In another embodiment of the present invention, the Hsp90 inhibitor isrepresented by structural formula (Ic):

In formula (Ic), R₁₈ is an optionally substituted cycloalkyl, andoptionally substituted cycloalkenyl, or a substituted alkyl, wherein thealkyl group is substituted with one or more substituents independentlyselected from the group consisting of an optionally substituted alkynyl,an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁. The remainder of thevariables in structural formula (Ic) have values defined above withreference to structural formula (Ia).

In yet another embodiment, the present invention is a method ofinhibiting Hsp90 in a mammal in need of such treatment. The methodcomprises administering to the mammal an effective amount of an Hsp90inhibitor disclosed herein.

Yet another embodiment of the present invention is a method ofinhibiting Hsp90 in a cell. The method comprises administering to thecell an effective amount of an Hsp90 inhibitor disclosed herein.

Yet another embodiment of the present invention is a method of treatinga proliferative disorder in a mammal comprising administering aneffective amount of an Hsp90 inhibitor disclosed herein.

Another embodiment of the present invention is a method of treatingcancer in a mammal. The method comprises administering to the mammal aneffective amount of an Hsp90 inhibitor disclosed herein.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising an Hsp90 inhibitor disclosed herein and apharmaceutically acceptable carrier. The pharmaceutical compositions canbe used in therapy, e.g., to inhibit Hsp90 activity in a mammal in needof such inhibition, to treat a mammal with a proliferative disorder, orto treat a mammal with cancer.

Yet another embodiment of the present invention is the use of an Hsp90inhibitor disclosed herein for the manufacture of a medicament forinhibiting Hsp90 in a mammal in need of such inhibition or for treatinga mammal with cancer.

The compounds shown in Tables 3-5 or compounds of the formulas disclosedherein, or tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof, inhibit theactivity of Hsp90 and, thereby cause the degradation of Hsp90 clientproteins. Hsp90 is necessary for the survival of normal eukaryoticcells. However, Hsp90 is over expressed in many tumor types indicatingthat it may play a significant role in the survival of cancer cells andthat cancer cells may be more sensitive to inhibition of Hsp90 thannormal cells. Thus, the compounds shown in Tables 3-5 or compounds ofthe formulas disclosed herein, or tautomers, pharmaceutically acceptablesalts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof,are useful treating proliferative disorders such as cancer.

Although chemotherapeutic agents initially cause tumor regression, mostagents that are currently used to treat cancer target only one pathwayto tumor progression. Therefore, in many instances, after treatment withone or more chemotherapeutic agents, a tumor develops multidrugresistance and no longer responses positively to treatment. One of theadvantages of inhibiting Hsp90 activity is that several of its clientproteins, which are mostly protein kinases or transcription factorsinvolved in signal transduction, have been shown to be involved in theprogression of cancer. Thus, inhibition of Hsp90 provides a method ofshort circuiting several pathways for tumor progression simultaneously.Therefore, treatment of tumors with an Hsp90 inhibitor of the inventioneither alone, or in combination with other chemotherapeutic agents, ismore likely to result in regression or elimination of the tumor, andless likely to result in the development of more aggressive multidrugresistant tumors than other currently available therapies.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the use of the compounds of theinvention to inhibit Hsp90 activity and for the treatment of aproliferative disorder, such as cancer. In particular, the presentinvention encompasses the use of compounds of the invention to slow orstop the growth of cancerous cells or to reduce or eliminate cancerouscells in a mammal.

In certain embodiments, the compounds of the invention can be used incombination with other chemotherapeutic agents and may help to preventor reduce the development of multidrug resistant cancerous cells in amammal. In this embodiment, the compounds of the invention may allow areduced efficacious amount of a second chemotherapeutic agent given to amammal, because compounds of the invention should inhibit thedevelopment of multidrug resistant cancerous cells.

I. Definition of Terms

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl andn-decyl; while saturated branched alkyls include isopropyl, sec-butyl,isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl,2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl,2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Theterms “C1-C6 alkyl” and “C1-C3 alkyls” mean saturated straight chain orbranched non-cyclic hydrocarbons having from 1 to 6 or from 1 to 3carbon atoms, respectively. Representative C1-C6 and C1-C3 alkyl groupsare those shown above having from 1 to 6 or 1 to 3 carbon atoms,respectively. Alkyl groups included in compounds of this invention maybe optionally substituted with one or more substituents.

As used herein, the term “heteroalkyl” refers to an alkyl as definedabove, in which one or more internal carbon atoms have been substitutedwith a heteroatom. Each heteroatom is independently selected fromnitrogen, which can be oxidized (e.g., N(O)), secondary, tertiary orquaternized; oxygen; and sulfur, including sulfoxide and sulfone.

As used herein, the term “alkenyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched C2-C10 alkenyls include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups may be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andhaving at least one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl,1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical having from 3 to 20 carbon atoms.Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, -cyclodecyl, octahydro-pentalenyl, and the like. Cycloalkylgroups may be optionally substituted with one or more substituents.

As used herein, the term “cycloalkenyl” means a mono- or poly-cyclicnonaromatic alkyl radical having at least one carbon-carbon double bondin the cyclic system and from 3 to 20 carbon atoms. Representativecycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl,cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl,cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl,1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups maybe optionally substituted with one or more substituents.

As used herein, the term “haloalkyl” means and alkyl group in which oneor more (including all) the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. The term “halomethyl” means a methyl in which one to threehydrogen radical(s) have been replaced by a halo group. Representativehaloalkyl groups include trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

As used herein, an “alkoxy” is an alkyl group which is attached toanother moiety via an oxygen linker.

As used herein, an “haloalkoxy” is an haloalkyl group which is attachedto another moiety via an oxygen linker.

As used herein, the term an “aromatic ring” or “aryl” means ahydrocarbon monocyclic or polycyclic radical in which at least one ringis aromatic. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substitutedwith one or more substituents. In one embodiment, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms, referred toherein as “(C6)aryl.”

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C1-C6)alkylene group. Representative aralkylgroups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.Aralkyl groups may be optionally substituted with one or moresubstituents.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “C1-C6 alkylene” refers to analkylene group that has from one to six carbon atoms. Straight chainC1-C6 alkylene groups are preferred. Non-limiting examples of alkylenegroups include methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), and the like. Alkylenegroups may be optionally substituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic (typicallyhaving 3- to 10-members) or a polycyclic (typically having 7- to20-members) heterocyclic ring system which is either a saturated ring ora unsaturated non-aromatic ring. A 3- to 10-membered heterocycle cancontain up to 5 heteroatoms; and a 7- to 20-membered heterocycle cancontain up to 7 heteroatoms. Typically, a heterocycle has at least oncarbon atom ring member. Each heteroatom is independently selected fromnitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; andsulfur, including sulfoxide and sulfone. The heterocycle may be attachedvia any heteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents. Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaromatic”, “heteroaryl” or like termsmeans a monocyclic or polycyclic heteroaromatic ring comprising carbonatom ring members and one or more heteroatom ring members. Eachheteroatom is independently selected from nitrogen, which can beoxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. Representative heteroaryl groups include pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, atriazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, theheteroaromatic ring is selected from 5-8 membered monocyclic heteroarylrings. The point of attachment of a heteroaromatic or heteroaryl ring toanother group may be at either a carbon atom or a heteroatom of theheteroaromatic or heteroaryl rings. Heteroaryl groups may be optionallysubstituted with one or more substituents.

As used herein, the term “C5 heteroaryl” means an aromatic heterocyclicring of 5 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, sulfur ornitrogen. Representative C5 heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.

As used herein, the term “C6 heteroaryl” means an aromatic heterocyclicring of 6 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, nitrogen orsulfur. Representative C6 heteroaryls include pyridyl, pyridazinyl,pyrazinyl, triazinyl, tetrazinyl and the like.

As used herein, the term “heteroaralkyl” means a heteroaryl group thatis attached to another group by a C1-C6 alkylene. Representativeheteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl,imidazol-4-yl-methyl and the like. Heteroaralkyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include any substituent which will form a stablecompound of the invention and not significantly lower the Hsp90inhibitory activity of the compound. Examples of substituents for analkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, a haloalkyl, —C(O)NR₄₀R₄₁, —C(S)NR₄₀R₄₁, —C(NR₃₂)NR₄₀R₄₁,—NR₄₂C(O)R₄₃, —NR₄₂C(S)R₄₃, —NR₄₂C(NR₃₂)R₄₃, halo, —OR₄₂, cyano, nitro,haloalkoxy, —C(O)R₄₂, —C(S)R₄₂, —C(NR₃₂)R₄₂, —NR₄₀R₄₁, —C(O)OR₄₂,—C(S)OR₄₂, —C(NR₃₂)OR₄₂, —OC(O)R₄₂, —OC(S)R₄₂, —OC(NR₃₂)R₄₂,—NR₄₂C(O)NR₄₀R₄₁, —NR₄₂C(S)NR₄₀R₄₁, —NR₄₂C(NR₃₂)NR₄₀R₄₁, —OC(O)NR₄₀R₄₁,—OC(S)NR₄₀R₄₁, —OC(NR₃₂)NR₄₀R₄₁, —NR₄₂C(O)OR₄₃, —NR₄₂C(S)OR₄₃,—NR₄₂C(NR₃₂) OR₄₃, —(O)_(h)R₄₂, —S(O)_(p)R₄₂, —NR₄₂S(O)_(p)R₄₂,—S(O)_(p)NR₄₀R₄₁, —OS(O)_(p)NR₄₀R₄₁, or —NR₄₂S(O)_(p)NR₄₀R₄₁, wherein

R₄₀ and R₄₁, for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₄₀ and R₄₁ taken together with the nitrogen to whichthey are attached is optionally substituted heterocyclyl or optionallysubstituted heteroaryl;

R₄₂ and R₄₃ for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; and

R₃₂, for each occurrence is, independently, H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, —C(O)R₄₂,—C(O)NR₄₀R₄₁, —S(O)_(p)R₄₂, or —S(O)_(p)NR₄₀R₄₁;

p and h, for each occurrence, is, independently, 0, 1 or 2.

Preferably, R₄₀, R₄₁, R₄₂, R₄₃ and R₃₂, for each occurrence, areindependently, H, an alkyl or phenyl group.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

As used herein, the term “lower” refers to a group having up to fouratoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 4 carbon atoms, “lower alkoxy” refers to “—O—(C1-C4)alkyl anda “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynylradical having from 2 to 4 carbon atoms, respectively.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as (without limitation) carboxy,hydroxy, thiol, and amino moieties) also include protected derivativesthereof. “Protected derivatives” are those compounds in which a reactivesite or sites are blocked with one or more protecting groups. Examplesof suitable protecting groups for hydroxyl groups include benzyl,methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate,and the like. Examples of suitable amine protecting groups includebenzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiolprotecting groups include benzyl, tert-butyl, acetyl, methoxymethyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of formulas (I) through (XV) and Tables 1-5or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph or prodrug thereof, and also include protected derivativesthereof.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers, diastereomers andgeometric isomers, that is, both the stereochemically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometricisomeric mixtures). In some cases, one enantiomer, diastereomer orgeometric isomer will possess superior activity or an improved toxicityor kinetic profile compared to other isomers. In those cases, suchenantiomers, diastereomers and geometric isomers of compounds of thisinvention are preferred.

As used herein, the term “polymorph” means solid crystalline forms of acompound of the present invention or complex thereof. Differentpolymorphs of the same compound can exhibit different physical, chemicaland/or spectroscopic properties. Different physical properties include,but are not limited to stability (e.g., to heat or light),compressibility and density (important in formulation and productmanufacturing), and dissolution rates (which can affectbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical characteristics (e.g.,tablets crumble on storage as a kinetically favored polymorph convertsto thermodynamically more stable polymorph) or both (e.g., tablets ofone polymorph are more susceptible to breakdown at high humidity).Different physical properties of polymorphs can affect their processing.For example, one polymorph might be more likely to form solvates ormight be more difficult to filter or wash free of impurities thananother due to, for example, the shape or size distribution of particlesof it.

As used herein, the term “hydrate” means a compound of the presentinvention or a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds offormulas (I) through (XV) and Tables 1-5 that comprise biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. Other examples ofprodrugs include derivatives of compounds of formulas (I) through (XV)and Tables 1-5 that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described by 1 Burger's Medicinal Chemistry and Drug Discovery(1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as improvedwater solubility, improved circulating half-life in the blood (e.g.,because of reduced metabolism of the prodrug), improved uptake, improvedduration of action, or improved onset of action; or 2) is itselfbiologically inactive but is converted in vivo to a biologically activecompound. Examples of biohydrolyzable amides include, but are notlimited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides,and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, “Hsp90” includes each member of the family of heat shockproteins having a mass of about 90-kiloDaltons. For example, in humansthe highly conserved Hsp90 family includes cytosolic Hsp90α and Hsp90βisoforms, as well as GRP94, which is found in the endoplasmic reticulum,and HSP75/TRAP1, which is found in the mitochondrial matrix.

The term “c-kit” or “c-kit kinase” refers to a membrane receptor proteintyrosine kinase which is preferably activated upon binding Stem CellFactor (SCF) to its extracellular domain (Yarden et al., 1987; Qiu etal., 1988). The full length amino acid sequence of a c-kit kinasepreferably is as set forth in Yarden, et al., 1987, EMBO J.,11:3341-3351; and Qiu, et al., 1988, EMBO J., 7:1003-1011, which areincorporated by reference herein in their entirety, including anydrawings. Mutant versions of c-kit kinase are encompassed by the term“c-kit” or “c-kit kinase” and include those that fall into two classes:(1) having a single amino acid substitution at codon 816 of the humanc-kit kinase, or its equivalent position in other species (Ma et al.,1999, J. Invest Dermatol., 112:165-170), and (2) those which havemutations involving the putative juxtamembrane z-helix of the protein(Ma, et al., 1999, J. Biol. Chem., 274:13399-13402). Both of thesepublications are incorporated by reference herein in their entirety,including any drawings.

As used herein, “Bcr-Abl” is a fusion protein that results from thetranslocation of gene sequences from c-ABL protein tyrosine kinase onchromosome 9 into BCR sequences on chromosome 22 producing thePhiladelphia chromosome. A schematic representation of human Bcr, Abl,and Bcr-Abl can be seen in FIG. 1 of U.S. patent application Ser. No.10/193,651, filed on Jul. 9, 2002, the entire teachings of which areincorporated herein by reference. Depending on the breaking point in theBcr gene, Bcr-Abl fusion proteins can vary in size from 185-230 kDa butthey must contain at least the OLI domain from Bcr and the TK domainfrom Abl for transforming activity. The most common Bcr-Abl geneproducts found in humans are P230 Bcr-Abl, P210 Bcr-Abl, and P190Bcr-Abl. P210 Bcr-Abl is characteristic of CML and P190 Bcr-Abl ischaracteristic of ALL.

FLT3 kinase is a tyrosine kinase receptor involved in the regulation andstimulation of cellular proliferation (see Gilliland et al., Blood(2002), 100:1532-42, the entire teachings of which are incorporatedherein by reference). The FLT3 kinase has five immunoglobulin-likedomains in its extracellular region as well as an insert region of75-100 amino acids in the middle of its cytoplasmic domain. FLT3 kinaseis activated upon the binding of the FLT3 ligand, which causes receptordimerization. Dimerization of the FLT3 kinase by FLT3 ligand activatesthe intracellular kinase activity as well as a cascade of downstreamsubstrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K),PLCγ, Erk2, Akt, MAPK, SHC, SHP2, and SHIP (see Rosnet et al., ActaHaematol. (1996), 95:218; Hayakawa et al., Oncogene (2000), 19:624;Mizuki et al., Blood (2000), 96:3907; and Gilliand et al., Curr. Opin.Hematol. (2002), 9: 274-81, the entire teachings of each of thesereferences are incorporated herein by reference). Both membrane-boundand soluble FLT3 ligand bind, dimerize, and subsequently activate theFLT3 kinase.

Normal cells that express FLT3 kinase include immature hematopoieticcells, typically CD34+ cells, placenta, gonads, and brain (see Rosnet,et al., Blood (1993), 82:1110-19; Small et al., Proc. Natl. Acad. Sci.U.S.A. (1994), 91:459-63; and Rosnet et al., Leukemia (1996), 10:238-48,the entire teachings of each of these references are incorporated hereinby reference). However, efficient stimulation of proliferation via FLT3kinase typically requires other hematopoietic growth factors orinterleukins. FLT3 kinase also plays a critical role in immune functionthrough its regulation of dendritic cell proliferation anddilferentiation (see McKenna et al., Blood (2000), 95:3489-97, theentire teachings of which are incorporated herein by reference).

Numerous hematologic malignancies express FLT3 kinase, the mostprominent of which is AML (see Yokota et al., Leukemia (1997),11:1605-09, the entire teachings of which are incorporated herein byreference). Other FLT3 expressing malignancies include B-precursor cellacute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias (see Rasko etal., Leukemia (1995), 9:2058-66, the entire teachings of which areincorporated herein by reference).

FLT3 kinase mutations associated with hematologic malignancies areactivating mutations. In other words, the FLT3 kinase is constitutivelyactivated without the need for binding and dimerization by FLT3 ligand,and therefore stimulates the cell to grow continuously. Two types ofactivating mutations have been identified: internal tandem duplications(ITDs) and point mutation in the activating loop of the kinase domain.As used herein, the term “FLT3 kinase” refers to both wild type FLT3kinase and mutant FLT3 kinases, such as FLT3 kinases that haveactivating mutations.

Compounds provided herein are useful in treating conditionscharacterized by inappropriate FLT3 activity such as proliferativedisorders. Inappropriate FLT3 activity includes, but is not limited to,enhanced FLT3 activity resulting from increased or de novo expression ofFLT3 in cells, increased FLT3 expression or activity, and FLT3 mutationsresulting in constitutive activation. The existence of inappropriate orabnormal FLT3 ligand and FLT3 levels or activity can be determined usingwell known methods in the art. For example, abnormally high FLT3 levelscan be determined using commercially available ELISA kits. FLT3 levelscan be determined using flow cytometric analysis, immunohistochemicalanalysis, and in situ hybridization techniques.

By “epidermal growth factor receptor” or “EGFR” as used herein is meant,any epidermal growth factor receptor (EGFR) protein, peptide, orpolypeptide having EGFR or EGFR family (e.g., HER1, HER2, HER3, and/orHER4) activity (such as encoded by EGFR Genbank Accession Nos. shown inTable I of U.S. patent application Ser. No. 10/923,354, filed on Aug.20, 2004, the entire teachings of which are incorporated herein byreference), or any other EGFR transcript derived from a EGFR gene and/orgenerated by EGFR translocation. The term “EGFR” is also meant toinclude other EGFR protein, peptide, or polypeptide derived from EGFRisoforms (e.g., HER1, HER2, HER3, and/or HER4), mutant EGFR genes,splice variants of EGFR genes, and EGFR gene polymorphisms.

As used herein, the terms “subject”, “patient” and “mammal” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),preferably a mammal including a non-primate (e.g., a cow, pig, horse,sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate(e.g., a monkey, chimpanzee and a human), and more preferably a human.In one embodiment, the subject is a non-human animal such as a farmanimal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat,guinea pig or rabbit). In a preferred embodiment, the subject is ahuman.

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g.,diabetic retinopathy or other retinopathies, cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated or prevented by the methods of the present inventioninclude, but are not limited to human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by the K562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cellline); myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

In a more preferred embodiment, proliferative disorders are lungcancers. Even more preferably, the disorder is non-small cell lungcarcinoma as exemplified, e.g. by the RERF, A549, NCI-H1993, andNCI-H460 cell lines.

In one embodiment, the disclosed method is believed to be particularlyeffective in treating subject with non-solid tumors such as multiplemyeloma. In another embodiment, the disclosed method is believed to beparticularly effective against T-leukemia (e.g., as exemplified byJurkat and CEM cell lines); B-leukemia (e.g., as exemplified by the SBcell line); promyelocytes (e.g., as exemplified by the HL-60 cell line);uterine sarcoma (e.g., as exemplified by the MES-SA cell line);monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cellline); and lymphoma (e.g., as exemplified by the U937 cell line).

In one embodiment, the disclosed method is believed to be particularlyeffective in treating subject with non-Hodgkin's lymphoma (NHL).Lymphomas are generally classified as either Hodgkin's disease (HD) ornon-Hodgkin's lymphomas (NHL). NHL differs from HD by the absence ofReed-Sternberg cells. The course of NHL is less predictable than HD andis more likely to spread to areas beyond the lymph nodes. NHL can befurther divided into B-cell NHL and T-cell NHL each of which can befurther categorized into a variety of different subtypes. For example,B-cell NHL includes Burkitt's lymphoma, follicular lymphoma, diffuselarge B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cellneoplasms, small lymphocytic lymphoma/chronic lymphocytic leukemia,mantle cell lymphoma, extranodal marginal zone B-cell lymphoma, andlymphoplamacytic lymphoma/Waldenstrom macroglobulinemia. T-cell NHLinclude anaplastic large-cell lymphoma, precursor-T-cell lymphoblasticleukemia/lymphoma, unspecified peripheral T-cell lymphoma, acutelymphoblastic leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, andmycosis fungoides.

Without wishing to be bound by any theory, it is believed that thecompounds of the invention are useful for treating NHLs, includingB-cell and T-cell NHLs, since Hsp90 is upregulated in many NHLs. Inparticular, in a survey of 412 cases of NHL in B-cell NHL, Hsp90 wasfound to be moderately to strongly over expressed in all cases ofBurkitt's lymphoma (5/5, 100%), and in a subset of follicular lymphoma(17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginalzone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%),small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%),mantle cell lymphoma (12/38, 32%), and lymphoplamacyticlymphoma/Waldenstrom macroglobulinemia (3/10, 30%). In addition, inT-cell NHL, Hsp90 was found to be moderately to strongly over expressedin a subset of anaplastic large-cell lymphoma (14/24, 58%),precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%),unspecified peripheral T-cell lymphoma (8/43, 23%), andangioimmunoblastic T-cell lymphoma (2/17, 12%). (See Valbuena, et al.,Modern Pathology (2005), 18:1343-1349, the entire teachings of which areincorporated herein by reference.)

Some of the disclosed methods can be particularly effective at treatingsubjects whose cancer has become “multi-drug resistant”. A cancer whichinitially responded to an anti-cancer drug becomes resistant to theanti-cancer drug when the anti-cancer drug is no longer effective intreating the subject with the cancer. For example, many tumors willinitially respond to treatment with an anti-cancer drug by decreasing insize or even going into remission, only to develop resistance to thedrug. Drug resistant tumors are characterized by a resumption of theirgrowth and/or reappearance after having seemingly gone into remission,despite the administration of increased dosages of the anti-cancer drug.Cancers that have developed resistance to two or more anti-cancer drugsare said to be “multi-drug resistant”. For example, it is common forcancers to become resistant to three or more anti-cancer agents, oftenfive or more anti-cancer agents and at times ten or more anti-canceragents.

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forblocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; pulmonary edema;asthma; nasal polyps; inflammatory bowel disease; periodontal disease;ascites; peritoneal adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation; angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis.

Vascular targeting can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Examples 3and 4.

As used herein, the term “angiogenesis” refers to a fundamental processof generating new blood vessels in tissues or organs. Angiogenesis isinvolved with or associated with many diseases or conditions, including,but not limited to: cancer; ocular neovascular disease; age-relatedmacular degeneration; diabetic retinopathy, retinopathy of prematurity;corneal graft rejection; neovascular glaucoma; retrolental fibroplasias;epidemic keratoconjunctivitis; Vitamin A deficiency; contact lensoverwear; atopic keratitis; superior limbic keratitis; pterygiumkeratitis sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;syphilis; Mycobacteria infections; lipid degeneration; chemical burns;bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpeszoster infections; protozoan infections; Kaposi's sarcoma; Mooren'sulcer; Terrien's marginal degeneration; mariginal keratolysis;rheumatoid arthritis; systemic lupus; polyarteritis; trauma; Wegener'ssarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid; radialkeratotomy; corneal graph rejection; diabetic retinopathy; maculardegeneration; sickle cell anemia; sarcoid; syphilis; pseudoxanthomaelasticum; Paget's disease; vein occlusion; artery occlusion; carotidobstructive disease; chronic uveitis/vitritis; mycobacterial infections;Lyme's disease; systemic lupus erythematosis; retinopathy ofprematurity; Eales' disease; Behcet's disease; infections causing aretinitis or choroiditis; presumed ocular histoplasmosis; Best'sdisease; myopia; optic pits; Stargardt's disease; pars planitis; chronicretinal detachment; hyperviscosity syndromes; toxoplasmosis; trauma andpost-laser complications; diseases associated with rubeosis(neovasculariation of the angle); diseases caused by the abnormalproliferation of fibrovascular or fibrous tissue including all forms ofproliferative vitreoretinopathy; rheumatoid arthritis; osteoarthritis;ulcerative colitis; Crohn's disease; Bartonellosis; atherosclerosis;Osler-Weber-Rendu disease; hereditary hemorrhagic telangiectasia;pulmonary hemangiomatosis; pre-eclampsia; endometriosis; fibrosis of theliver and of the kidney; developmental abnormalities (organogenesis);skin discolorations (e.g., hemangioma, nevus flammeus, or nevussimplex); wound healing; hypertrophic scars, i.e., keloids; woundgranulation; vascular adhesions; cat scratch disease (Rochele ninaliaquintosa); ulcers (Helicobacter pylori); keratoconjunctivitis;gingivitis; periodontal disease; epulis; hepatitis; tonsillitis;obesity; rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis;pneumonia; interstitial pulmonary fibrosis; pulmonary edema;neurodermitis; thyroiditis; thyroid enlargement; endometriosis;glomerulonephritis; gastritis; inflammatory bone and cartilagedestruction; thromboembolic disease; and Buerger's disease.

Anti-angiogenesis can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Examples 5and 6.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from, for example, an acid and a basic group of one of thecompounds of formulas (I) through (XV) and Tables 1-5. Illustrativesalts include, but are not limited, to sulfate, citrate, acetate,oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, besylate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of formulas (I) through (XV) and Tables 1-5 having an acidicfunctional group, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of formulas (I) through (XV) and Tables 1-5having a basic functional group, such as an amine functional group, anda pharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude, but are not limited to, hydrogen sulfate, citric acid, aceticacid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr),hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid,lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbicacid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconicacid, glucaronic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds of formulas (I)through (XV) and Tables 1-5. The term solvate includes hydrates (e.g.,hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and thelike).

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, i.e.,non-toxic, non-inflammatory, non-immunogenic and devoid of otherundesired reactions upon the administration to a subject. Standardpharmaceutical formulation techniques can be employed, such as thosedescribed in Remington's Pharmaceutical Sciences, ibid. Suitablepharmaceutical carriers for parenteral administration include, forexample, sterile water, physiological saline, bacteriostatic saline(saline containing about 0.9% mg/ml benzyl alcohol), phosphate-bufferedsaline, Hank's solution, Ringer's-lactate and the like. Methods forencapsulating compositions (such as in a coating of hard gelatin orcyclodextran) are known in the art (Baker, et al., “Controlled Releaseof Biological Active Agents”, John Wiley and Sons, 1986).

As used herein, the term “effective amount” refers to an amount of acompound of this invention which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of a proliferativedisorder, prevent the advancement of a proliferative disorder, cause theregression of a proliferative, prevent the recurrence, development,onset or progression of a symptom associated with a proliferativedisorder, or enhance or improve the prophylactic or therapeuticeffect(s) of another therapy. The precise amount of compoundadministered to a subject will depend on the mode of administration, thetype and severity of the disease or condition and on the characteristicsof the subject, such as general health, age, sex, body weight andtolerance to drugs. It will also depend on the degree, severity and typeof cell proliferation, and the mode of administration. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors. When co-administered with other agents, e.g., whenco-administered with an anti-cancer agent, an “effective amount” of thesecond agent will depend on the type of drug used. Suitable dosages areknown for approved agents and can be adjusted by the skilled artisanaccording to the condition of the subject, the type of condition(s)being treated and the amount of a compound of the invention being used.In cases where no amount is expressly noted, an effective amount shouldbe assumed.

Non-limiting examples of an effective amount of a compound of theinvention are provided herein below. In a specific embodiment, theinvention provides a method of preventing, treating, managing, orameliorating a proliferative disorder or one or more symptoms thereof,said methods comprising administering to a subject in need thereof adose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, atleast 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more ofone or more compounds of the invention once every day, preferably, onceevery 2 days, once every 3 days, once every 4 days, once every 5 days,once every 6 days, once every 7 days, once every 8 days, once every 10days, once every two weeks, once every three weeks, or once a month.

The dosages of a chemotherapeutic agents other than compounds of theinvention, which have been or are currently being used to prevent,treat, manage, or ameliorate a proliferative disorder, or one or moresymptoms thereof, can be used in the combination therapies of theinvention. Preferably, dosages lower than those which have been or arecurrently being used to prevent, treat, manage, or ameliorate aproliferative disorder, or one or more symptoms thereof, are used in thecombination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorder, or one or more symptomsthereof, can obtained from any reference in the art including, but notlimited to, Hardman et al., eds., 1996, Goodman & Gilman's ThePharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, NewYork; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical EconomicsCo., Inc., Montvale, N.J., which are incorporated herein by reference inits entirety.

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a proliferative disorder, or the amelioration of one or moresymptoms (preferably, one or more discernible symptoms) of aproliferative disorder resulting from the administration of one or moretherapies (e.g., one or more therapeutic agents such as a compound ofthe invention). In specific embodiments, the terms “treat”, “treatment”and “treating” refer to the amelioration of at least one measurablephysical parameter of a proliferative disorder, such as growth of atumor, not necessarily discernible by the patient. In other embodimentsthe terms “treat”, “treatment” and “treating” refer to the inhibition ofthe progression of a proliferative disorder, either physically by, e.g.,stabilization of a discernible symptom, physiologically by, e.g.,stabilization of a physical parameter, or both. In other embodiments theterms “treat”, “treatment” and “treating” refer to the reduction orstabilization of tumor size or cancerous cell count.

As used herein, the terms “prevent”, “prevention” and “preventing” referto the reduction in the risk of acquiring or developing a givenproliferative disorder, or the reduction or inhibition of the recurrenceor a proliferative disorder. In one embodiment, a compound of theinvention is administered as a preventative measure to a patient,preferably a human, having a genetic predisposition to any of thedisorders described herein.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment, management, oramelioration of a proliferative disorder or one or more symptomsthereof. In certain embodiments, the term “therapeutic agent” refers toa compound of the invention. In certain other embodiments, the term“therapeutic agent” refers does not refer to a compound of theinvention. Preferably, a therapeutic agent is an agent which is known tobe useful for, or has been or is currently being used for the treatment,management, prevention, or amelioration a proliferative disorder or oneor more symptoms thereof.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent), which is more effective than the additive effects ofthe therapies. A synergistic effect of a combination of therapies (e.g.,a combination of prophylactic or therapeutic agents) permits the use oflower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject with a proliferativedisorder. The ability to utilize lower dosages of a therapy (e.g., aprophylactic or therapeutic agent) and/or to administer said therapyless frequently reduces the toxicity associated with the administrationof said therapy to a subject without reducing the efficacy of saidtherapy in the prevention, management or treatment of a proliferativedisorder. In addition, a synergistic effect can result in improvedefficacy of agents in the prevention, management or treatment of aproliferative disorder. Finally, a synergistic effect of a combinationof therapies (e.g., a combination of prophylactic or therapeutic agents)may avoid or reduce adverse or unwanted side effects associated with theuse of either therapy alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapy (e.g., a prophylactic or therapeuticagent). Side effects are always unwanted, but unwanted effects are notnecessarily adverse. An adverse effect from a therapy (e.g.,prophylactic or therapeutic agent) might be harmful or uncomfortable orrisky. Side effects include, but are not limited to fever, chills,lethargy, gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the term “in combination” refers to the use of more thanone therapies (e.g., one or more prophylactic and/or therapeuticagents). The use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a proliferative disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compound ofthe invention) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent such as ananti-cancer agent) to a subject with a proliferative disorder, such ascancer.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a proliferativedisorder or one or more symptoms thereof.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use and includeprophylactic and therapeutic protocols. As used herein, the terms“manage,” “managing,” and “management” refer to the beneficial effectsthat a subject derives from a therapy (e.g., a prophylactic ortherapeutic agent), which does not result in a cure of the disease. Incertain embodiments, a subject is administered one or more therapies(e.g., one or more prophylactic or therapeutic agents) to “manage” adisease so as to prevent the progression or worsening of the disease.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to a chiral center inthe molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of the invention.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or diastereomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are administered inisolated form or as the isolated form in a pharmaceutical composition.As used herein, “isolated” means that the compounds of the invention areseparated from other components of either (a) a natural source, such asa plant or cell, preferably bacterial culture, or (b) a syntheticorganic chemical reaction mixture. Preferably, the compounds of theinvention are purified via conventional techniques. As used herein,“purified” means that when isolated, the isolate contains at least 95%,preferably at least 98%, of a compound of the invention by weight of theisolate either as a mixture of stereoisomers or as a diastereomeric orenantiomeric pure isolate.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation. The invention can be understood morefully by reference to the following detailed description andillustrative examples, which are intended to exemplify non-limitingembodiments of the invention.

II. Compounds of the Invention

In one embodiment, a compound of the present invention is represented bythe structural formula (Ia-c):

In formulas (Ia-c):

ring A is an aryl or a heteroaryl, optionally further substituted withone or more substituents in addition to R₃. Preferably, Ring A isrepresented one of the following structural formulas:

where n is 0, 1, 2, 3 or 4; x is 0 or 1; and n+x is less than or equalto 4.

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. Morepreferably, R₁ is —OH, —SH, or —NHR₇. Even more preferably, R₁, is —SHor —OH;

R₂ is an optionally substituted phenyl group. Preferably, R₂ issubstituted with one or more group represented by R₃₀, wherein R₃₀, foreach occurrence, are independently an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. More preferably, R₂ is an optionally substituted indolylgroup or a phenyl group substituted with NR₁₀R₁₁ and optionally with atleast one other substitutent represented by R₃₀;

R₃ is —OH, —SH, —NR₇H, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈,—C(O)SH, —S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. In another embodiment, —OR₂₆ and —SR₂₆, are additionalvalues for R₃. Preferably, R₃ is —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. More preferably, R₃ is —OH, —SH, or —NHR₇. Even morepreferably, R₃ is —SH or —OH;

R₅ is an optionally substituted heteroaryl; an optionally substituted 6to 14-membered aryl; a bicyclic 9-member heterocycle optionallysubstituted at any substitutable nitrogen or carbon atoms. In anotheralternative, R₅ is represented by R₁₈, which is an optionallysubstituted cycloalkyl, and optionally substituted cycloalkenyl, or asubstituted alkyl, wherein the alkyl group is substituted with one ormore substituents independently selected from the group consisting of anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

R₅ in structural formula (Ia) is preferably represented by structuralformula (IIa):

In structural formula (IIa), R₉, for each occurrence, is independently asubstituent selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken togetherwith the carbon atoms to which they are attached form a fused ring, andm is zero or an integer from 1 to 7. More preferably, substituent R₅ instructural formula (IIa) is represented by one of structural formulas(IIb) and (IIc):

In structural formulas (IIb) and (IIc) R₉ is as defined for formula(IIa), q is zero or an integer from 1 to 7 and u is zero or an integerfrom 1 to 8. The remainder of the variables in structural formulas(IIa), (IIb) and (IIc) has values defined above with reference tostructural formula (I).

In another alternative, R₅ in structural formula (Ia) is represented bythe structural formula (IIIa):

In structural formula (IIIa), R₃₃ is —H, a halo, lower alkyl, a loweralkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;R₃₄ is H, a lower alkyl, or a lower alkylcarbonyl; and ring B and ring Care optionally substituted with one or more substituents. The remainderof the variables has values defined above with reference to structuralformula (Ia).

In another alternative, R₅ in structural formula (Ia) is selected from agroup listed in Table 1.

TABLE 1 Number Substituent R₅ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

In the structural formulas of Table 1:

X₆, for each occurrence, is independently CH, CR₉, N,N(O), N⁺(R₁₇),provided that at least three X₆ groups are independently selected fromCH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N,N(O), N⁺(R₁₇),provided that at least three X₇ groups are independently selected fromCH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, CR₉R₉, O, S,S(O)_(p), NR₇, or NR₁₇,

X₉, for each occurrence, is independently N or CH;

X₁₀, for each occurrence, is independently CH, CR₉, N,N(O), N⁺(R₁₇),provided that at least one X₁₀ is selected from CH and CR₉;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and

R₁₇, for each occurrence, is independently —H, an alkyl, an aralkyl,—C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁.

Preferred R₅ groups from Table 1 are selected from the group consistingof an optionally substituted indolyl, an optionally substitutedbenzoimidazolyl, an optionally substituted indazolyl, an optionallysubstituted 3H-indazolyl, an optionally substituted indolizinyl, anoptionally substituted quinolinyl, an optionally substitutedisoquinolinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, anoptionally substituted benzothiazolyl, an optionally substitutedbenzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, anoptionally substituted thiazolo[4,5-c]pyridinyl, an optionallysubstituted thiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pyridinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pyridinyl, an optionally substitutedoxazolo[5,4-b]pyridinyl, an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotriazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.

In another alternative, R₅ in structural formula (Ia) is a bicyclic9-member heterocycle optionally substituted at any substitutablenitrogen or carbon atoms.

In another alternative, R₅ in structural formula (Ia) is selected fromthe group consisting of:

In formulas (IVa), (IVb) and (IVc):

X₁₁, for each occurrence, is independently CH, CR₉, N,N(O), or N⁺(R₁₇),provided that at least one X₁₁ is N,N(O), or N⁺(R₁₇) and at least twoX₁₁ groups are independently selected from CH and CR₉;

X₁₂, for each occurrence, is independently CH, CR₉, N,N(O), N⁺(R₁₇),provided that at least one X₁₂ group is independently selected from CHand CR₉;

X₁₃, for each occurrence, is independently O, S, S(O)_(p), NR₇, or NR₁₇;

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; or two R₉ groups taken together with the carbon atomsto which they are attached form a fused ring; and R₁₇, for eachoccurrence, is independently an alkyl or an aralkyl. The remainder ofthe variables have values defined above with reference to structuralformula (I).

In a preferred embodiment, the compound of the invention is representedby structural formula (Va):

In structural formula (Va):

X₁₀₁ is O, S, or NR₁₀₂ and X₁₀₂ is CR₁₀₄ or N. Preferably, X₁₀₁ is NR₁₀₂and X₁₀₂ is CR₁₀₄. Alternatively, X₁₀₁ is NR₁₀₂ and X₁₀₂ is N;

Y, for each occurrence, is independently N or CR₁₀₃;

Y₁₀₁ is N or CR₁₀₅;

Y₁₀₂ is N, C or CR₁₀₆;

R₁ is —OH, —SH, or NHR₇. Preferably, R₁ is —OH or —SH;

R₆ is —H, —OH, —SH, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₆ is selected from the group consisting of—H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, and C1-C6 cycloalkoxy,more preferably from the group consisting of —H, methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;

R₁₀₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;preferably, R₁₀₂ is selected from the group consisting of —H, a C1-C6alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂, and —C(O)OH, wherein R₂₇ is —Hor a C1-C6 alkyl or from the group consisting of —H, methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tent-butyl,n-pentyl, n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂;

R₁₀₃ and R₁₀₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₁₀₃ and R₁₀₄ taken together with the carbon atomsto which they are attached form an optionally substituted cycloalkenyl,an optionally substituted aryl, an optionally substituted heterocyclyl,or an optionally substituted heteroaryl; preferably, R₁₀₃ and R₁₀₄ areindependently, selected from the group consisting of —H, methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy;

R₁₀₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; preferably, R₁₀₅is selected from the group consisting of —H, —OH, —SH, —NH₂, a C1-C6alkoxy, a C1-C6 alkyl amino, and a C1-C6 dialkyl amino, more preferablyfrom the group consisting of —H, —OH, methoxy and ethoxy; and

R₁₀₆, for each occurrence, is independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

The remainder of the variables of the compounds of structural formula(Va) has values defined above with reference to structural formula (Ia).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (Va), X₁₀₁ is NR₁₀₂, R₁₀₂ is selected from thegroup consisting of —H, a C1-C6 alkyl, a C1-C6 cycloalkyl, —C(O)N(R₂₇)₂,and —C(O)OH, each R₂₇ is independently —H or a C1-C6 alkyl and thevalues for the remainder of the variables are as described above forformula (Va).

In a second preferred set of values for the variables of the Hsp90inhibitor represented by formula (Va), X₁₀₁ is NR₁₀₂, R₁₀₂ is selectedfrom the group consisting of —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tent-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂ and the valuesfor the remainder of the variables are as described above for formula(Va).

In third preferred set of values for the variables of the Hsp90inhibitor represented by formula (Va), X₁₀₂ is CR₁₀₄; Y is CR₁₀₃; andR₁₀₃ and R₁₀₄ together with the carbon atoms to which they are attachedform a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.Preferably, R₁₀₃ and R₁₀₄ together with the carbon atoms to which theyare attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl and the valuesfor the remainder of the variables are as described above for formula(Va).

In fourth preferred set of values for the variables of the Hsp90inhibitor represented by formula (Va), R₁ is —OH or —SH and the valuesfor the remainder of the variables are as described above for formula(Va).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by structural formula (Vb):

where X₁₀₃ is CR₁₀₄ or N and the remainder of the variables is definedabove with reference with structural formulas (Va).

In another preferred embodiment, the Hsp90 inhibitor of the invention isrepresented by structural formula selected from (VIa-c)-(VIIIa-c):

The values for the variables in structural formulas (VIa-c)-(VIIIa-c)are as described in structural formula (Ia-c).

In one preferred set of values for the variables of the Hsp90 inhibitorrepresented by structural formulas (VIa-c)-(VIIIa-c):

R₅ is as described for structural formula (Ia), (IIa-c) or (Va-c) or astructural formula from Table 1;

R₆ and R₂₅, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR)₂;

n in structural formula (VIa-c) is zero or an integer from 1 to 4; n instructural formula (VIIa-c) is zero or an integer from 1 to 3;

x is 0 or 1;

n+x in structural formula (VI) is less than or equal to 4; and

the remainder of the variables in formulas (VIa-c)-(VIIIa-c) have valuesdefined above with reference to structural formula (Ia-c).

A second preferred set of values for the variables of the Hsp90inhibitor represented by structural formula (VIa-c), (VIIa-c) or(VIIIa-c) is provided in the following paragraphs:

R₂₅ is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH,—NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃,—OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and k is 1, 2, 3, or 4; and R₁, R₃, R₆ and the remainderof the variables are as described in the first preferred set of valuesfor the variables in structural formulas (VIa-c)-(VIIIa-c). Preferably,R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

A third preferred set of values for the variables of the Hsp90 inhibitorrepresented by formula (VIa-c), (VIIa-c) or (VIIIa-c) is provided in thefollowing paragraphs:

R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇;

R₆ is an optionally substituted alkyl or cycloalkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, cyano, halo,nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy,haloalkoxy, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₁ and R₃ and the remainder of the variables are asdescribed in the second preferred set of values for the variables instructural formulas (VIa-c)-(VIIIa-c).

In a fourth preferred set of values for the variables of StructuralFormulas (VIa-c)-(VIIIa-c):

R₁ is —SH or —OH;

R₃ and R₂₅ are —OH;

R₆ is a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl, or —NR₁₀R₁₁; and

The remainder of the variables are as defined in Structural Formula(Ia-c).

In another preferred embodiment, the Hsp90 inhibitor is represented by astructural formula selected from (IXa)-(IXf):

In formulas (IXa) and (IXb):

R₅ is as described for structural formula (Ia), (IIa-c) or (Va-c) or astructural formula from Table 1;

X₃ and X₄ are each, independently, N,N(O), N⁺(R₁₇), CH or CR₆;

X₅ is O, S, NR₁₇, CH₂, CH(R₆), C(R₆)₂, CH═CH, CH═CR₆, CR₆═CH, CR₆═CR₆,CH═N, CR₆═N, CH═N(O), CR₆═N(O), N═CH, N═CR₆, N(O)═CH, N(O)═CR₆,N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₆, CH═N⁺(R₁₇), CR₆═N⁺(R₁₇), or N═N, provided thatat least one X₃, X₄ or X₅ is a heteroatom;

R₆, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₁₇, for each occurrence, is independently an alkyl or an aralkyl; and nis zero or an integer from 1 to 4; and

the remainder of the variables has values defined above with referenceto structural formulas (Ia-c).

Preferably, Hsp90 inhibitor of structural formulas (IXa)-(IXf) areselected from Table 2a-c.

TABLE 2a Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

TABLE 2b Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

TABLE 2c Number Compound 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

The values for the variables for the formulas in Tables 2a-c are asdefined for structural formulas (IXa-f). Preferably, R₆ is a halo, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OH, —SH, —NHR₇, —(CH₂)_(k)OH,—(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃, —NHCH₃, —OCH₂CH₂OH,—OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH, —SCH₂CH₂NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; and k is 1, 2, 3, or 4.

In another preferred embodiment, the Hsp90 inhibitor of the presentinvention is represented by structural formula (X):

R₆ and R₂₅, for each occurrence, are independently an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇,—C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂. Preferably, R₆ is selected from an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl,haloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, —OR₇,—SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇ and R₂₅ is as just described. The values for theremainder of the variables are as described for structural formulas(Ia-c).

In another preferred embodiment, the Hsp90 inhibitors is represented bystructural formulas (XIa) and (XIb):

The variables in formulas (XIa) and (XIb) are defined above withreference to formula (X).

A first preferred set of values for the variables of structural formula(XIa) and (XIb) is provided in the following paragraph:

R₁, R₃ or R₂₅ are each independently selected from —OH, —SH, —NHR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂, and p, R₆, R₇, R₈, R₁₀, R₁₁ and R₃₀ are as described forstructural formula (X). Preferably, when R₁, R₃ and R₂₅ have thesevalues, R₁₀ and R₁₁ are preferably each independently a hydrogen, aC1-C6 straight or branched alkyl, optionally substituted by —OH, —CN,—SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and p, R₆, R₇, and R₃₀ are asdescribed for structural formula (X). More preferably, when R₁, R₃, R₁₀,R₁₁, and R₂₅ have these values, R₆ is preferably a C1-C6 alkyl, a C1-C6haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl ora C3-C6 cycloalkyl; and p, R₇, R₈ and R₃₀ are as described forstructural formula (X).

A second preferred set of values for the variables of structural formula(XIa) and (XIb) is provided in the following paragraph:

R₁ and R₃ are each independently —OH or —SH; R₆ is preferably a C1-C6alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6alkyl sulfanyl or a C3-C6 cycloalkyl; R₁₀ and R₁₁ are preferably eachindependently a hydrogen, a C1-C6 straight or branched alkyl, optionallysubstituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl,alkylamino, dialkylamino or a cycloalkyl; or R₁₀ and R₁₁ taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted nonaromatic, nitrogen-containing heterocyclyl; R₂₅ is —OH,—SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇,—SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇,—SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇,—OP(O)(OR₇)₂ or —SP(O)(OR₇)₂; and p, R₇ R₈ and R₃₀ are as described forstructural formula (X). Preferably, R₃₀ is a —OH, —SH, halogen, cyano, aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl and the remainder of the variables are as just described.

A third preferred set of values for the variables of structural formula(XIa) and (XIb) is provided in the following paragraph:

R₁, R₃ and R₂₅ are independently —SH or —OH; R₆ is cyclopropyl orisopropyl; R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6straight or branched alkyl, optionally substituted by —OH, —CN, —SH,amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or acycloalkyl; or R₁₀ and R₁₁ taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted nonaromatic,nitrogen-containing heterocyclyl; and R₃₀ is —OH, —SH, halogen, cyano, aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6alkyl sulfanyl. Preferably, R₃₀ is a methyl, ethyl, propyl, isopropyl,methoxy or ethoxy. More preferably, R₁, R₃, R₆, R₂₅ and R₃₀ are as justdescribed and R₁₀ and R₁₁ are each independently a hydrogen, methyl,ethyl, propyl, isopropyl, or taken together with the nitrogen to whichthey are attached, are:

wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another preferred embodiment, the Hsp90 inhibitor is represented bystructural formulas (XIIa-b):

The values for the variables in structural formulas (XIIa-b) are asdescribed for structural formulas (IXc-d). Preferably, R₃₀ is anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂. More preferably, R₃₀ is an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, cyano, halo, nitro, an optionally substitutedcycloalkyl, haloalkyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,—C(O)NR₁₀R₁₁, —C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, or —S(O)_(p)R₇.

In another preferred embodiment, the Hsp90 inhibitor is represented bystructural formulas (XIIIa-d):

The values of the variables in structural formulas (XIIIa-d) are definedabove with reference to structural formulas (XIIa-b).

A first preferred set of values for the variables in structural formulas(XIIIa-d) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH or —SH, or —HNR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂;

R₆, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, —OH, —SH, —HNR₇,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂. Preferably, R₆ is a C1-C6 alkyl, a C1-C6 haloalkyl, aC1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6cycloalkyl; and

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(XIIIa-d) are as described for structural formulas (XIIa-b). Preferably,R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R₁₀and R₁₁ taken together with the nitrogen to which they are attached forma substituted or unsubstituted nonaromatic, nitrogen-containingheterocyclyl.

In another preferred embodiment, the Hsp90 inhibitor is represented bystructural formulas (XIVa-p):

The values of the variables in structural formulas (XIVa-p) are definedabove with reference to structural formulas (XIIIa-d).

A first preferred set of values for the variables in structural formulas(XIVa-p) are as described in the following paragraphs:

R₁ and R₃ are each independently —OH or —SH, or —HNR₇;

R₆, is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl;

R₁₀ and R₁₁ and the remainder of the variables in structural formulas(XIIIa-d) are as described for structural formulas (XIIa-b). Preferably,R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R₁₀and R₁₁ taken together with the nitrogen to which they are attached forma substituted or unsubstituted nonaromatic, nitrogen-containingheterocyclyl; and

R₃₀ and the remainder of the variables in structural formulas (XIVa-p)are as described for structural formulas (XIIIa-d). Preferably, R₃₀ is—OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.

A second preferred set of values for the variables in structuralformulas (XIVa-p) are as described in the following paragraphs:

R₁ and R₃ are independently —SH or —OH;

R₆ is cyclopropyl or isopropyl;

R₁₀ and R₁₁ are each independently a hydrogen, a C1-C6 straight orbranched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R₁₀and R₁₁ taken together with the nitrogen to which they are attached forma substituted or unsubstituted nonaromatic, nitrogen-containingheterocyclyl;

R₃₀ is —OH, —SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. Preferably, R₃₀ is amethyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and

the remainder of the variables are as described for formulas (IXa-b).More preferably,

-   -   R₁₀ and R₁₁ are each independently a hydrogen, methyl, ethyl,        propyl, isopropyl, or taken together with the nitrogen to which        they are attached, are:

-   -   wherein R₃₅ is —H, a C1-C4 alkyl or a C1-C4 acyl.

In another embodiment, the Hsp90 inhibitor of the present invention isrepresented by structural formulas (XVa) and (XVb):

In formulas (XVa) and (XVb):

X₁₄ is O, S, or NR₇. Preferably, X₁₄ is O;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂.Preferably, R₁ is —OH, —SH, or —NHR₇;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈,—C(O)SH, —S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl. Preferably, R₂₁ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl. Alternatively,R₂₁ is

wherein

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl or heteroaryl, an optionally substitutedaralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to which theyare attached, form an optionally substituted heteroaryl or heterocyclyl;and

R₃₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

n and q are independently an integer from 0 to 4; and

x is 0 or 1, provided that n+x less than or equal to 4.

R₂₂, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted H, alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, ahaloalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁. Preferably, R₂₂ is analkyl, an aralkyl, —C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently a substituentselected from the group consisting of H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 0, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

III. Exemplary Compounds of the Present Invention

Tables 3, 4 and 5 provides examples of the compounds of the presentinvention.

TABLE 3 Number Structure 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

TABLE 4 Number Structure 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

TABLE 5 Number Structure 1.

2.

3.

It is understood that the compounds of the present invention, includingcompounds of formulas (I) through (XV) and Tables 1-5 can be purified,isolated, obtained and used in a form of a pharmaceutically acceptablesalt, a solvate, a clathrate, a tautomer or a prodrug.

For example, a compound of formula (I) can undergo the followingtautomerization:

where X⁰ is O, S, or NR₇. It is understood that where a structuralformula is depicted, all possible tautomeric forms of the compound areencompassed within that formula.

Similarly, prodrugs, i.e. compounds which can be metabolized orhydrolyzed in vivo to a compound of the present invention areencompassed by the present description. For example, the followingembodiments of a compound of formula (I) can be produced in vivo in thefollowing reaction:

One skilled in the art will understand that other hydrolyzableprotecting groups can be employed with the compounds of the presentinvention to obtain prodrugs encompassed by the present description.IV. Methods for Making Compounds of the Invention

Compounds of the invention can be obtained via standard, well-knownsynthetic methodology, see e.g., March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992.

For example, compound 40 of Table 4 was prepared according to the Scheme(1):

In Scheme (1), compound 2 was prepared from compound 1 in 33% yieldaccording to reference paper “J. Amer. Chem. Soc., 1935, 57, 1658-1659”,the relevant teachings of which are incorporated herein by reference.Conversion of compound 2 in the presence of dimethyl sulphate andpotassium carbonate in acetone gave compound 3 in 96% yield afterchromatography on silica gel. Compound 4 was prepared by coupling ofcompound 3 with methyl naphthalene acetate using sodium methoxide asbase. The isolation yield is 29%. Proton NMR of compound 4 indicatedequilibrium between β-keto and enolate.

Compound 4 (90 mg) was treated with BBr₃ (20 equiv.) in DCM.Purification of the crude by chromatography gave compound 5 as pinksolid (46 mg).

Preparation of compound 6 was conducted using compound 5 (30 mg) in thepresence of 0.20 mL of hydrazine (45 equiv) in DME (2 mL) at reflux 2hours. Chromatography of the crude product gave compound 6 as a lightpurple solid (25 mg, 74% yield). ¹H-NMR (Acetone-d₆) δ (ppm): 7.89 (t,J=7.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 1H), 7.3-7.5 (m, 4H), 6.42 (s, 1H),6.34 (s, 1H), 1.9 (m, 2H), 0.32 (t, J=7.5 Hz, 2H); ESMS calcd. forC₂₁H₁₈N₂O₃: 346.1; Found: 347.6 (M+1)⁺.

V. Uses of Compounds of the Invention

The present invention is directed to therapies which involveadministering one of more compounds of the invention, and compositionscomprising said compounds to a subject, preferably a human subject, toinhibit the activity of Hsp90 or to prevent, treat, manage, orameliorate a proliferative disorder, such as cancer, or one or moresymptoms thereof.

In one embodiment, the present invention is directed to treating cancersin which aberrant expression and/or activation of c-kit has beenimplicated as a contributing factor. The method comprises administeringto a patient an effective amount of a compound represented by formulas(I)-(XV), including Tables 1-5.

In one embodiment, the present invention is directed to treating cancersin which expression of Bcr-Abl has been implicated as a contributingfactor. The method comprises administering to a patient an effectiveamount of a compound represented by formulas (I)-(XV), including Tables1-5.

In one embodiment, the present invention is directed to treating cancersin which aberrant expression and/or activation of flt-3 has beenimplicated as a contributing factor. The method comprises administeringto a patient an effective amount of a compound represented by formulas(I)-(XV), including Tables 1-5.

In one embodiment, the present invention is directed to treating cancersin which aberrant expression and/or activation of EGFR has beenimplicated as a contributing factor. The method comprises administeringto a patient an effective amount of a compound represented by formulas(I)-(XV), including Tables 1-5.

In one embodiment, the present invention is directed to treating cancersin which Hsp90 is over expressed compared with normal cells. The methodcomprises administering to a patient an effective amount of a compoundrepresented by formulas (I)-(XV), including Tables 1-5. Examples ofcancers in which Hsp90 is over expressed include difuse large B-celllymphomas (DLBCL).

In one aspect, the invention provides a method of inhibiting theactivity of Hsp90 in a cell, comprising administering to the cell aneffective amount of a compound represented by formulas (I)-(XV),including Tables 1-5. In one embodiment, the compound is administered toa cell in a subject, preferably a mammal, and more preferably a human.

In another aspect, the invention provides a method of treating orpreventing a proliferation disorder in a mammal, comprisingadministering to the mammal an effective amount of a compoundrepresented by formulas (I)-(XV), including Tables 1-5. In oneembodiment, the compound is administered to a human to treat or preventa proliferative disorder. In another embodiment, the proliferationdisorder is cancer. In another embodiment, the compound is administeredwith one or more additional therapeutic agents. In a preferredembodiment, the additional therapeutic agent is an anticancer agent.

In another aspect, the invention provides a method for treating cancerin a mammal, comprising administering to the mammal an effective amountof a compound represented by formulas (I)-(XV), including Tables 1-5. Inone embodiment, the compound is administered to a human to treat orprevent cancer. In another embodiment, the compound is administered withone or more additional therapeutic agents. In a preferred embodiment,the one or more additional therapeutic agents are anticancer agents.

In another aspect, the invention provides a method for treating a c-kitassociated cancer in a mammal, comprising administering to the mammal aneffective amount of a compound represented by formulas (I)-(XV),including Tables 1-5. In one embodiment, the compound is administered toa human to treat or prevent the c-kit associated cancer. In anotherembodiment, the compound is administered with one or more additionaltherapeutic agents. In a preferred embodiment, the one or moreadditional therapeutic agents are anticancer agents.

In another aspect, the invention provides a method for treating aBcr-Abl associated cancer in a mammal, comprising administering to themammal an effective amount of a compound represented by formulas(I)-(XV), including Tables 1-5. In one embodiment, the compound isadministered to a human to treat or prevent the Bcr-Abl associatedcancer. In another embodiment, the compound is administered with one ormore additional therapeutic agents. In a preferred embodiment, the oneor more additional therapeutic agents are anticancer agents.

In another aspect, the invention provides a method for treating a flt3associated cancer in a mammal, comprising administering to the mammal aneffective amount of a compound represented by formulas (I)-(XV),including Tables 1-5. In one embodiment, the compound is administered toa human to treat or prevent the flt3 associated cancer. In anotherembodiment, the compound is administered with one or more additionaltherapeutic agents. In a preferred embodiment, the one or moreadditional therapeutic agents are anticancer agents.

In another aspect, the invention provides a method for treating an EGFRassociated cancer in a mammal, comprising administering to the mammal aneffective amount of a compound represented by formulas (I)-(XV),including Tables 1-5. In one embodiment, the compound is administered toa human to treat or prevent the EGFR associated cancer. In anotherembodiment, the compound is administered with one or more additionaltherapeutic agents. In a preferred embodiment, the one or moreadditional therapeutic agents are anticancer agents.

In another aspect, the invention provides a method for treating a cancerin a mammal which is characterized by the upregulation of Hsp90 comparedto normal cells of the same type, comprising administering to the mammalan effective amount of a compound represented by formulas (I)-(XV),including Tables 1-5. In one embodiment, the compound is administered toa human to treat or prevent the cancer associated with the upregulationof Hsp90. In another embodiment, the cancer associated with theupregulation of Hsp90 is DLBCL. In another embodiment, the compound isadministered with one or more additional therapeutic agents. In apreferred embodiment, the one or more additional therapeutic agents areanticancer agents.

In another aspect, the invention provides a method for treating orinhibiting angiogenesis in a subject in need thereof, comprisingadministering to the subject an effective amount of a compoundrepresented by formulas (I)-(XV), including Tables 1-5.

In another aspect, the invention provides a method of blocking,occluding, or otherwise disrupting blood flow in neovasculature,comprising contacting the neovasculature with an effective amount of acompound represented by formulas (I)-(XV), including Tables 1-5. In oneaspect, the neovasculature is in a subject and blood flow in theneovasculature is blocked, occluded, or otherwise disrupted in thesubject by administering to the subject an effective amount of acompound represented by formulas (I)-(XV), including Tables 1-5. In oneaspect, the subject is human.

1. c-Kit Associated Cancers

SCF binding to the c-kit protects hematopoietic stem and progenitorcells from apoptosis (Lee, et al., 1997, J. Immunol., 159:3211-3219, theentire teachings of which are incorporated herein by reference), therebycontributing to colony formation and hematopoiesis. Expression of c-kitis frequently observed in acute myelocytic leukemia (AML) and sometimesobserved in acute lymphocytic leukemia (ALL) (for reviews, see Sperling,et al., 1997, Haemat., 82:617-621; Escribano, et al., 1998, Leuk.Lymph., 30:459-466, the entire teachings of which are incorporated byreference). Although c-kit is expressed in the majority of AML cells,its expression does not appear to be prognostic of disease progression(Sperling, et al, 1997, Haemat. 82:617-621, the entire teachings ofwhich are incorporated by reference). However, SCF protected AML cellsfrom apoptosis induced by chemotherapeutic agents (Hassan, et al., 1996,Acta. Hem., 95:257-262, the entire teachings of which are incorporatedherein by reference). Therefore, degradation of c-kit caused by theinhibition of Hsp90 by the compounds of the invention will enhance theefficacy of these agents and may induce apoptosis of AML cells.

The clonal growth of cells from patients with myelodysplastic syndrome(Sawada, et al., 1996, Blood, 88:319-327, the entire teachings of whichare incorporated herein by reference) or chronic myelogenous leukemia(CML) (Sawai, et al., 1996, Exp. Hem., 2:116-122, the entire teachingsof which are incorporated herein by reference) was found to besignificantly enhanced by SCF in combination with other cytokines CML ischaracterized by expansion of Philadelphia chromosome positive cells ofthe marrow (Verfaillie, et al., 1998, Leuk., 12:136-138, the entireteachings of which are incorporated herein by reference), which appearsto primarily result from inhibition of apoptotic death (Jones, 1997,Curr. Opin. Onc., 9:3-7, the entire teachings of which are incorporatedherein by reference). The product of the Philadelphia chromosome,BCR-ABL, has been reported to mediate inhibition of apoptosis (Bedi, etal., 1995, Blood, 86:1148-1158, the entire teachings of which areincorporated herein by reference). Since BCR-ABL and the c-kit RTK bothinhibit apoptosis and p62 dok has been suggested as a substrate(Carpino, et al., 1997, Cell, 88:197-204, the entire teachings of whichare incorporated herein by reference), it is possible that clonalexpansion mediated by these kinases occurs through a common signalingpathway. However, c-kit has also been reported to interact directly withBCR-ABL (Hallek, et al., 1996, Brit. J Haem., 94:5-16, the entireteachings of which are incorporated herein by reference), which suggeststhat c-kit may have a more causative role in CML pathology. Therefore,degradation of c-kit caused by the inhibition of Hsp90 by the compoundsof the invention will prove useful in the treatment of CML.

Normal colorectal mucosa does not express c-kit (Bellone, et al., 1997,J. Cell Physiol., 172:1-11, the entire teachings of which areincorporated herein by reference). However, c-kit is frequentlyexpressed in colorectal carcinoma (Bellone, et al., 1997, J. CellPhysiol., 172: 1-11, the entire teachings of which are incorporatedherein by reference), and autocrine loops of SCF and c-kit have beenobserved in several colon carcinoma cell lines (Toyota, et al., 1993,Turn. Biol., 14:295-302; Lahm, et al., 1995, Cell Growth & Differ.,6:1111-1118; Bellone, et al., 1997, J. Cell Physiol., 172:1-11, theentire teachings of each of these references are incorporated herein byreference). Furthermore, disruption of the autocrine loop by the use ofneutralizing antibodies (Lahm, et al., 1995, Cell Growth & Differ.,6:1111-1118, the entire teachings of which are incorporated herein byreference) and downregulation of c-kit and/or SCF significantly inhibitscell proliferation (Lahm, et al., 1995, Cell Growth & Differl.,6:1111-1118; Bellone, et al., 1997, J. Cell Physiol., 172:1-11, theentire teachings of each of these references are incorporated herein byreference).

SCF/c-kit autocrine loops have been observed in gastric carcinoma celllines (Turner, et al., 1992, Blood, 80:374-381; Hassan, et al., 1998,Digest. Dis. Science, 43:8-14, the entire teachings of each of thesereferences are incorporated herein by reference), and constitutive c-kitactivation also appears to be important for gastrointestinal stromaltumors (GISTs). GISTs are the most common mesenchymal tumor of thedigestive system. More than 90% of GISTs express c-kit, which isconsistent with the putative origin of these tumor cells frominterstitial cells of Cajal (ICCs) (Hirota, et al., 1998, Science,279:577-580, the entire teachings of which are incorporated herein byreference). The c-kit expressed in GISTs from several different patientswas observed to have mutations in the intracellular juxtamembrane domainleading to constitutive activation (Hirota, et al., 1998, Science279:577-580, the entire teachings of which are incorporated herein byreference). Therefore, degradation of c-kit caused by the inhibition ofHsp90 by the compounds of the invention will be an efficacious means forthe treatment of these cancers.

Male germ cell tumors have been histologically categorized intoseminomas, which retain germ cell characteristics, and nonseminomaswhich can display characteristics of embryonal differentiation. Bothseminomas and nonseminomas are thought to initiate from a preinvasivestage designated carcinoma in situ (CIS) (Murty, et al., 1998, Sem.Oncol., 25:133-144, the entire teachings of which are incorporatedherein by reference). Both c-kit and SCF have been reported to beessential for normal gonadal development during embryogenesis (Loveland,et al., 1997, J. Endocrinol., 153:337-344, the entire teachings of whichare incorporated herein by reference). Loss of either the receptor orthe ligand resulted in animals devoid of germ cells. In postnataltestes, c-kit has been found to be expressed in Leydig cells andspermatogonia, while SCF was expressed in Sertoli cells (Loveland, etal., 1997, J. Endocrinol., 153:337-344, the entire teachings of whichare incorporated herein by reference). Testicular tumors develop fromLeydig cells with high frequency in transgenic mice expressing humanpapilloma virus 16 (HPV16) E6 and E7 oncogenes (Kondoh, et al., 1991, J.Virol., 65:3335-3339; Kondoh, et al., 1994, J. Urol., 152:2151-2154, theentire teachings of each of these references are incorporated herein byreference). These tumors express both c-kit and SCF, and an autocrineloop may contribute to the tumorigenesis (Kondoh, et al., 1995,Oncogene, 10:341-347, the entire teachings of which are incorporatedherein by reference) associated with cellular loss of functional p53 andthe retinoblastoma gene product by association with E6 and E7 (Dyson, etal., 1989, Science, 243:934-937; Werness, et al., 1990, Science,248:76-79; Scheffner, et al., 1990, Cell, 63:1129-1136, the entireteachings of each of these references are incorporated herein byreference). Defective signaling mutants of SCF (Kondoh, et al., 1995,Oncogene, 10:341-347, the entire teachings of which are incorporatedherein by reference) or c-kit (Li, et al., 1996, Canc. Res.,56:4343-4346, the entire teachings of which are incorporated herein byreference) inhibited formation of testicular tumors in mice expressingHPV16 E6 and E7. Since c-kit kinase activation is pivotal totumorigenesis in these animals, the compounds of the invention whichinhibit Hsp90 and thereby cause the degradation of c-kit will be usefulfor preventing or treating testicular tumors associated with humanpapilloma virus.

Expression of c-kit on germ cell tumors shows that the receptor isexpressed by the majority of carcinomas in situ and seminomas, but c-kitis expressed in only a minority of nonseminomas (Strohmeyer, et al.,1991, Canc. Res., 51:1811-1816; Rajpert-de Meyts, et al., 1994, Int. J.Androl., 17:85-92; Izquierdo, et al., 1995, J. Pathol., 177:253-258;Strohmeyer, et al., 1995, J. Urol., 153:511-515; Bokenmeyer, et al.,1996, J. Cance. Res., Clin. Oncol., 122:301-306; Sandlow, et al., 1996,J. Androl., 17:403-408, the entire teachings of each of these referencesare incorporated herein by reference). Therefore, degradation of c-kitcaused by the inhibition of Hsp90 by the compounds of the invention willbe an efficacious means for the treatment of these cancers.

SCF and c-kit are expressed throughout the central nervous system ofdeveloping rodents, and the pattern of expression suggests a role ingrowth, migration and differentiation of neuroectodermal cells.Expression of SCF and c-kit have also been reported in the adult brain(Hamel, et al., 1997, J. Neuro-Onc., 35:327-333, the entire teachings ofwhich are incorporated herein by reference). Expression of c-kit hasalso been observed in normal human brain tissue (Tada, et al. 1994, J.Neuro., 80:1063-1073, the entire teachings of which are incorporatedherein by reference). Glioblastoma and astrocytoma, which define themajority of intracranial tumors, arise from neoplastic transformation ofastrocytes (Levin, et al., 1997, Principles & Practice of Oncology,2022-2082, the entire teachings of which are incorporated herein byreference). Expression of c-kit has been observed in glioblastoma celllines and tissues (Berdel, et al., 1992, Canc. Res., 52:3498-3502; Tada,et al., 1994, J. Neuro., 80:1063-1073; Stanulla, et al., 1995, Act.Neuropath., 89:158-165, the entire teachings of each of these referencesare incorporated herein by reference). Therefore, degradation of c-kitcaused by the inhibition of Hsp90 by the compounds of the invention willbe an efficacious means for the treatment of these cancers.

The association of c-kit with astrocytoma pathology is less clear.Reports of expression of c-kit in normal astrocytes have been made(Natali, et al., 1992, Int. J. Canc., 52:197-201, the entire teachingsof which are incorporated herein by reference), (Tada, et al. 1994, J.Neuro., 80:1063-1073, the entire teachings of which are incorporatedherein by reference), while others report it is not expressed (Kristt,et al., 1993, Neuro., 33:106-115, the entire teachings of which areincorporated herein by reference). In the former case, high levels ofc-kit expression in high grade tumors were observed (Kristt, et al.,1993, Neuro., 33:106-115, the entire teachings of which are incorporatedherein by reference), whereas in the latter case researchers were unableto detect any expression in astrocytomas. In addition, contradictoryreports of c-kit and SCF expression in neuroblastomas also exist. Onestudy found that neuroblastoma cell lines often express SCF, but rarelyexpress c-kit. In primary tumors, c-kit was detected in about 8% ofneuroblastomas, while SCF was found in 18% of tumors (Beck, et al.,1995, Blood, 86:3132-3138, the entire teachings of which areincorporated herein by reference). In contrast, other studies (Cohen, etal., 1994, Blood, 84:3465-3472, the entire teachings of which areincorporated herein by reference) have reported that all 14neuroblastoma cell lines examined contained c-kit/SCF autocrine loops,and expression of both the receptor and ligand were observed in 45% oftumor samples examined. In two cell lines, anti-c-kit antibodiesinhibited cell proliferation, suggesting that the SCF/c-kit autocrineloop contributed to growth (Cohen, et al., 1994, Blood, 84:3465-3472,the entire teachings of which are incorporated herein by reference).Therefore, degradation of c-kit caused by the inhibition of Hsp90 by thecompounds of the invention will be an efficacious means for treatingsome cancers of the central nervous system.

2. Bcr-Abl Associated Cancers

The Philadelphia chromosome which generates the fusion protein Bcr-Ablis associated with the bulk of chronic myelogenous leukemia (CML)patients (more than 95%), 10-25% of acute lymphocytic leukemia (ALL)patients, and about 2-3% of acute myelogenous leukemias (AML). Inaddition, Bcr-Abl is a factor in a variety of other hematologicalmalignancies, including granulocytic hyperplasia resembling CML,myelomonocytic leukemia, lymphomas, and erythroid leukemia (see Lugo, etal., MCB (1989), 9:1263-1270; Daley, et al., Science (1990),247:824-830; and Honda, Blood (1998), 91:2067-2075, the entire teachingsof each of these references are incorporated herein by reference).

A number of different kinds of evidence support the contention thatBcr-Abl oncoproteins, such as p210 and p185 BCR-ABL, are causativefactors in these leukemias (Campbell and Arlinghaus, “Current Status ofBcr Gene Involvement with Human Leukemia”, In: Advances in CancerResearch, Eds. Klein, VandeWoude, Orlando, Fla. Academic Press, Inc.,57:227-256, 1991, the entire teachings of which are incorporated hereinby reference). The malignant activity is due in large part to theBcr-Abl protein's highly activated protein tyrosine kinase activity andits abnormal interaction with protein substrates (Arlinghaus et al., In:UCLA Symposia on Molecular and Cellular Biology New Series, AcuteLymphoblastic Leukemia, Eds. R. P. Gale, D. Hoelzer, New York, N.Y.,Alan R. Liss, Inc., 108:81-90, 1990, the entire teachings of which areincorporated herein by reference). The Bcr-Abl oncoprotein p210 Bcr-Ablis associated with both CML and ALL, whereas the smaller oncoprotein,p185 BCR-ABL, is associated with ALL patients, although some CMLpatients also express p185 (Campbell et al., 1991).

3. FLT3 Associated Cancers

FLT3 associated cancers are cancers in which inappropriate FLT3 activityis detected. FLT3 associated cancers include hematologic malignanciessuch as leukemia and lymphoma. In some embodiments FLT3 associatedcancers include acute myelogenous leukemia (AML), B-precursor cell acutelymphoblastic leukemia, myelodysplastic leukemia, T-cell acutelymphoblastic leukemia, mixed lineage leukemia (MLL), or chronicmyelogenous leukemia (CML).

4. EGFR Associated Cancers

EGFR associated cancers are cancers in which inappropriate EGFR activity(e.g., overexpression of EGFR or mutation of EGFR which causesconstitutive tyrosine kinase activity) has been implicated as acontributing factor. Inappropriate EGFR activity has been associatedwith an adverse prognosis in a number of human cancers, such asneuroblastoma, intestine carcinoma such as rectum carcinoma, coloncarcinoma, familiary adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma,larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary glandcarcinoma, gastric carcinoma, adenocarcinoma, medullary thyroideacarcinoma, papillary thyroidea carcinoma, renal carcinoma, kidneyparenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpuscarcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma,bronchial carcinoma, small cell lung carcinoma, non-small cell lungcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma and plasmocytoma.

In particular, EGFR appears to have an important role in the developmentof human brain tumors. A high incidence of overexpression,amplification, deletion and structural rearrangement of the gene codingfor EGFR has been found in biopsies of brain tumors. In fact, theamplification of the EGFR gene in glioblastoma multiforme tumors is oneof the most consistent genetic alterations known, with EGFR beingoverexpressed in approximately 40% of malignant gliomas and EGFRvIIImutation being found in about 50% of all glioblastomas.

In addition to gliomas, abnormal EGFR expression has also been reportedin a number of squamous epidermoid cancers and breast cancers.Interestingly, evidence also suggests that many patients with tumorsthat over-express EGFR have a poorer prognosis than those having tumorsthat do not over-express EGFR.

Non-small cell lung cancer (NSCLC) includes squamous cell carcinomas,adenocarcinoma, bronchioloalveolar carcinoma (BAC), and large cellundifferentiated carcinoma. A subset of patients with NSCLC have beenshown to have mutations in the tyrosine kinase domain of EGFR which isthought to be necessary for the maintenance of the disease. Treatment ofthis subset of patients with NSCLC with gefitinib, a tyrosine kinaseinhibitor which targets EGFR, has shown rapid and dramatic clinicalresponse.

Consequently, therapeutic strategies that can potentially inhibit orreduce the aberrant expression of EGFR are of great interest aspotential anti-cancer agents.

5. Combination Therapies and Treatment of Refractory Cancers

The invention also provides methods of preventing, treating, managing,or ameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof, said methods comprising administering to a subject inneed thereof one or more compounds of the invention and one or moreother therapies (e.g., one or more prophylactic or therapeutic agentsthat are currently being used, have been used, are known to be useful orin development for use in the prevention, treatment or amelioration of aproliferative disorder, such as cancer, or one or more symptomsassociated with said proliferative disorder).

The prophylactic or therapeutic agents of the combination therapies ofthe invention can be administered sequentially or concurrently. In aspecific embodiment, the combination therapies of the invention compriseone or more compounds and at least one other therapy (e.g., anotherprophylactic or therapeutic agent) which has the same mechanism ofaction as said compounds. In another specific embodiment, thecombination therapies of the invention comprise one or more compounds ofthe invention and at least one other therapy (e.g., another prophylacticor therapeutic agent) which has a different mechanism of action thansaid compounds. In certain embodiments, the combination therapies of thepresent invention improve the prophylactic or therapeutic effect of oneor more compounds of the invention by functioning together with thecompounds to have an additive or synergistic effect. In certainembodiments, the combination therapies of the present invention reducethe side effects associated with the therapies (e.g., prophylactic ortherapeutic agents). In certain embodiments, the combination therapiesof the present invention reduce the effective dosage of one or more ofthe therapies.

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject, preferably a human subject, in the samepharmaceutical composition. In alternative embodiments, the prophylacticor therapeutic agents of the combination therapies can be administeredconcurrently to a subject in separate pharmaceutical compositions. Theprophylactic or therapeutic agents may be administered to a subject bythe same or different routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to prevent, treat, manage, or ameliorate a proliferativedisorder, such as cancer, or one or more symptom thereof. In accordancewith the invention, pharmaceutical compositions of the invention mayalso comprise one or more other agents (e.g., prophylactic ortherapeutic agents which are currently being used, have been used, orare known to be useful in the prevention, treatment or amelioration of aproliferative disorder or a symptom thereof).

The invention provides methods for preventing, managing, treating orameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof in a subject refractory (either completely orpartially) to existing agent therapies for such a proliferativedisorder, said methods comprising administering to said subject a doseof an effective amount of one or more compounds of the invention and adose of an effective amount of one or more therapies (e.g., one or moreprophylactic or therapeutic agents useful for the prevention, treatment,management, or amelioration of a proliferative disorder or a symptomthereof). The invention also provides methods for preventing, treating,managing, or ameliorating a proliferative disorder or a symptom thereofby administering one or more compounds of the invention in combinationwith any other therapy(ies) to patients who have proven refractory toother therapies but are no longer on these therapies.

The compounds of the invention and/or other therapies can beadministered to a subject by any route known to one of skill in the art.Examples of routes of administration include, but are not limited to,parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,inhalation), intranasal, transdermal (topical), transmucosal, and rectaladministration.

VI. Agents Useful in Combination with the Compounds of the Invention

Without wishing to be bound by theory, it is believed that the compoundsof the invention can be particularly effective at treating subjectswhose cancer has become multi-drug resistant. Although chemotherapeuticagents initially cause tumor regression, most agents that are currentlyused to treat cancer target only one pathway to tumor progression.Therefore, in many instances, after treatment with one or morechemotherapeutic agents, a tumor develops multidrug resistance and nolonger responds positively to treatment. One of the advantages ofinhibiting Hsp90 activity is that several of its client proteins, whichare mostly protein kinases or transcription factors involved in signaltransduction, have been shown to be involved in the progression ofcancer. Thus, inhibition of Hsp90 provides a method of short circuitingseveral pathways for tumor progression simultaneously. Therefore, it isbelieved that treatment of cancer with an Hsp90 inhibitor of theinvention either alone, or in combination with other chemotherapeuticagents, is more likely to result in regression or elimination of thetumor, and less likely to result in the development of more aggressivemultidrug resistant tumors than other currently available therapies.

In one embodiment, the compounds of the invention can be administeredwith agents that are tyrosine kinase inhibitors (e.g., gefitinib orerlotinib which inhibit EGFR tyrosine kinase activity). In anotherembodiment, the compounds of the invention can be administered topatients whose cancer has become resistant to a tyrosine kinaseinhibitor (e.g., gefitinib or erlotinib). In this embodiment, thecompounds of the invention can be administered either alone or incombination with the tyrosine kinase inhibitor.

In another embodiment, the compounds of the invention are useful fortreating patients with hematological cancers that have become resistantto Imatinib, a chemotherapeutic agent that acts by inhibiting tyrosinekinase activity of Bcr-Abl. In patients with CML in the chronic phase,as well as in a blast crisis, treatment with Imatinib typically willinduce remission. However, in many cases, particularly in those patientswho were in a blast crisis before remission, the remission is notdurable because the Bcr-Abl fusion protein develops mutations in thetyrosine kinase domain that cause it to be resistance to Imatinib. (SeeNimmanapalli, et al., Cancer Research (2001), 61:1799-1804; and Gone, etal., Blood (2002), 100:3041-3044, the entire teachings of each of thesereferences are incorporated herein by reference). Compounds of theinvention act by inhibiting the activity of Hsp90 which disruptBcr-Abl/Hsp90 complexes. When Bcr-Abl is not complex to Hsp90 it israpidly degraded. Therefore, compounds of the invention are effective intreating Imatinib resistant leukemias since they act through a differentmechanism than Imatinib. Compounds of the invention can be administeredalone or with Imatinib in patients who have a Bcr-Abl associated cancerthat is not resistant to Imatinib or to patients whose cancer has becomeresistant to Imatinib.

Anticancer agents that can be co-administered with the compounds of theinvention include Taxol™, also referred to as “paclitaxel”, is awell-known anti-cancer drug which acts by enhancing and stabilizingmicrotubule formation, and analogs of Taxol™, such as Taxotere™.Compounds that have the basic taxane skeleton as a common structurefeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Other examples of anti-cancer agents which act by arresting cells in theG2-M phases due to stabilized microtubules include without limitationthe following marketed drugs and drugs in development:

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with the compounds of the invention include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

VII. Compositions and Methods for Administering Therapies

The present invention provides compositions for the treatment,prophylaxis, and amelioration of proliferative disorders, such ascancer. In a specific embodiment, a composition comprises one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition of the invention comprises one or more prophylactic ortherapeutic agents other than a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrugthereof. In another embodiment, a composition of the invention comprisesone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate or prodrug thereof, and one or moreother prophylactic or therapeutic agents. In another embodiment, thecomposition comprises a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and formulated in such a way thata given pharmaceutical composition or dosage form can be used to treator prevent proliferative disorders, such as cancer. Preferredpharmaceutical compositions and dosage forms comprise a compound offormulas (I)-(XV), including Tables 1-5 or a pharmaceutically acceptableprodrug, salt, solvate, clathrate, hydrate, or prodrug thereof,optionally in combination with one or more additional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton, Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

VIIA. Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

VIIB. Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormulas (I)-(XV), including Tables 1-5, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, inspheroids which further comprise microcrystalline cellulose and,optionally, hydroxypropylmethyl-cellulose coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose. Such extended releaseformulations can be prepared according to U.S. Pat. No. 6,274,171, theentirely of which is incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formulas (I)-(XV), includingTables 1-5, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, by weight, about 50% to about 94%microcrystalline cellulose, NF, by weight, and optionally from about0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP,wherein the spheroids are coated with a film coating compositioncomprised of ethyl cellulose and hydroxypropylmethylcellulose.

VIIC. Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

VIID. Transdermal, Topical, And Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton, Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

VIIE. Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of aproliferative disorders, such as cancer, or one or more symptomsthereof, will vary with the nature and severity of the disease orcondition, and the route by which the active ingredient is administered.The frequency and dosage will also vary according to factors specificfor each patient depending on the specific therapy (e.g., therapeutic orprophylactic agents) administered, the severity of the disorder,disease, or condition, the route of administration, as well as age,body, weight, response, and the past medical history of the patient.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Suitable regiments can beselected by one skilled in the art by considering such factors and byfollowing, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent proliferative disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such proliferative disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a proliferative disorders, such as cancer, or one or moresymptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's bodyweight. In another embodiment, the dosage of the composition of theinvention or a compound of the invention administered to prevent, treat,manage, or ameliorate a proliferative disorders, such as cancer, or oneor more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg,0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7mg, 0.25 mgto 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg,1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003,Medical Economics Co., Inc., Montvale, N.J., which are incorporatedherein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered less than 5 minutesapart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart,at about 1 to about 2 hours apart, at about 2 hours to about 3 hoursapart, at about 3 hours to about 4 hours apart, at about 4 hours toabout 5 hours apart, at about 5 hours to about 6 hours apart, at about 6hours to about 7 hours apart, at about 7 hours to about 8 hours apart,at about 8 hours to about 9 hours apart, at about 9 hours to about 10hours apart, at about 10 hours to about 11 hours apart, at about 11hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96hours apart, or 96 hours to 120 hours part. In one embodiment, two ormore therapies (e.g., prophylactic or therapeutic agents) areadministered within the same patient visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 μg/kg,preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

EXEMPLIFICATION Example 1 A Compound of the Present Inhibits of Hsp90 inMalachite Green Assay

HspSP90 protein is obtained from Stressgen (Cat#SPP-770). Assay buffer:100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl₂. Malachite green (0.0812%w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (P1097) are obtainedfrom Sigma. A Malachite Green Assay (see Methods Mol Med, 2003, 85:149for method details) is used for examination of ATPase activity of Hsp90protein. Briefly, HspSP90 protein in assay buffer (100 mM Tris-HCl,Ph7.4, 20 mM KCl, 6 mM MgCl₂) is mixed with ATP alone (negative control)or in the presence of Geldanamycin (a positive control) or a compound ofthe invention in a 96-well plate. Malachite green reagent is added tothe reaction. The mixtures is incubated at 37° C. for 4 hours and sodiumcitrate buffer (34% w/v sodium citrate) was added to the reaction. Theplate is read by an ELISA reader with an absorbance at 620 nm.

Example 2 Inhibition of Hsp90 Activity by a Compound of the PresentInvention Results in Degradation of Her2

A. Cells and Cell Culture

Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) andMCF-7 breast carcinoma (HTB-22) from American Type Culture Collection,Va., USA were grown in Dulbecco's modified Eagle's medium with 4 mML-glutamine and antibiotics (100 IU/ml penicillin and 100 ug/mlstreptomycine; GibcoBRL). To obtain exponential cell growth, cells weretrypsinized, counted and seeded at a cell density of 0.5×10⁶ cells/mlregularly, every 3 days. All experiments were performed on day 1 aftercell passage.

B. Degradation of Her2 in Cells after Treatment with a Compound of theInvention

1. Method 1

BT-474 cells are treated with 0.5 μM, 2 μM, or 5 μM of 17AAG (a positivecontrol) or 0.5 μM, 2 μM, or 5 μM of a compound of the inventionovernight in DMEM medium. After treatment, each cytoplasmic sample isprepared from 1×10⁶ cells by incubation of cell lysis buffer (#9803,cell Signaling Technology) on ice for 10 minutes. The resultingsupernatant used as the cytosol fractions is dissolved with samplebuffer for SDS-PAGE and run on a SDS-PAGE gel, blotted onto anitrocellulose membrane by using semi-dry transfer. Non-specific bindingto nitrocellulose is blocked with 5% skim milk in TBS with 0.5% Tween atroom temperature for 1 hour, then probed with anti-Her2/ErB2 mAb (rabbitIgG, #2242, Cell Signaling) and anti-Tubulin (T9026, Sigma) ashousekeeping control protein. HRP-conjugated goat anti-rabbit IgG (H+L)and HRP-conjugated horse anti-mouse IgG (H+L) are used as secondary Ab(#7074, #7076, Cell Signaling) and LumiGLO reagent, 20× Peroxide (#7003,Cell Signaling) is used for visualization.

Her2, an Hsp90 client protein, is expected to be degraded when cells aretreated with compounds of the invention. 0.5 μM of 17AAG, a known Hsp90inhibitor which is used as a positive control, causes partialdegradation of Her2.

2. Method 2

MV-4-11 cells (20,000 cells/well) were cultured in 96-well plates andmaintained at 37° C. for several hours. The cells were treated with acompound of the invention or 17AAG (a positive control) at variousconcentrations and incubated at 37° C. for 72 hours. Cell survival wasmeasured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. # CK04).

The IC₅₀ range for Her2 degradation by compound 40 is listed below inTable 6.

TABLE 6 IC₅₀ range of compounds of the invention for inhibition of Hsp90IC₅₀ Range Compound Number 10 to 100 uM Compound 40 of Table 4C. Fluorescent Staining of Her2 on the Surface of Cells Treated with aCompound of the Invention

After treatment with a compound of the invention, cells are washed twicewith 1×PBS/1% FBS, and then stained with anti-Her2-FITC (#340553, BD)for 30 min at 4° C. Cells are then washed three times in FACS bufferbefore the fixation in 0.5 ml 1% paraformadehydrede. Data is acquired ona FACSCalibur system. Isotype-matched controls are used to establish thenon-specific staining of samples and to set the fluorescent markers. Atotal 10,000 events are recorded from each sample. Data are analysed byusing CellQuest software (BD Biosciences).

D. Apoptosis Analysis

After treatment with the compounds of the invention, cells are washedonce with 1×PBS/1% FBS, and then stained in binding buffer withFITC-conjugated Annexin V and Propidium iodide (PI) (all obtained fromBD Biosciences) for 30 min at 4° C. Flow cytometric analysis isperformed with FACSCalibur (BD Biosciences) and a total 10,000 eventsare recorded from each sample. Data is analyzed by using CellQuestsoftware (BD Biosciences). The relative fluorescence is calculated aftersubtraction of the fluorescence of control.

Example 3 Necrosis in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 ml of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 ml of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 ml ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10(6) cells per flask are seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

Tumors are then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically requires 1 week followingimplantation. Animals with oblong, very small or large tumors arediscarded, and only animals carrying tumors that display consistentgrowth rates are selected for studies. Tumor volumes (V) are calculatedby caliper measurement of the width (W), length (L) and thickness (T) oftumors using the following formula: V=0.5236×(L×W×T). Animals arerandomized into treatment groups so that each group had median tumorvolumes of ˜100 mm³ at the start of dosing.

To formulate a compound of the invention in DRD, a stock solution of thetest article is prepared by dissolving an appropriate amount of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) isalso prepared by first heating 100% Cremophore RH40 at 50-60° C. untilliquefied and clear, diluting 1:5 with 100% D5W, reheating again untilclear and then mixing well. This solution is stored at room temperaturefor up to 3 months prior to use. To prepare a DRD formulation fordosing, the DMSO stock solution is diluted 1:10 with 20% CremophoreRH40. The final DRD formulation for dosing contains 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article.

Tumor-bearing animals are given a single intravenous (i.v.) bolusinjections of either DRD vehicle or a compound of the inventionformulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr afterdrug treatment, tumors are excised, cut in half and fixed overnight in10% neutral-buffered formalin. Each tumor is embedded in paraffin withthe cut surfaces placed downwards in the block, and rough cut until acomplete section is obtained. From each tumor, 5 μM serial sections areprepared and stained with hematoxylin and eosin. Slides are evaluatedmanually using light microscopy with a 10×10 square gridded reticle. Thepercentage of necrosis in a tumor is quantified at 200× magnification byscoring the total number of grid squares containing necrosis and thetotal number of grid squares containing viable tumor cells.

It is expected that compounds of the invention will result in anincrease in necrotic tissue in the center of EMT6 tumors relative to thebaseline necrosis observed in vehicle treated tumors. As would beexpected for a vascular targeting mechanism of action, rapid onset ofnecrosis is consistent with there being a loss of blood flow to tumorsresulting in hypoxia and tumor cell death.

Example 4 Vascular Disrupting Activities in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 mL of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10⁶ cells/mL in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 mL of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

For the Evans Blue dye assay, tumors are permitted to develop in vivountil the majority reach 40-90 mm³ in tumor volume (to minimize theextent of tumor necrosis), which typically require 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors are discarded and only animals carrying tumors that displayconsistent growth rates are selected for use. Tumor volumes (V) arecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals are randomized into treatment groups so that at the start ofdosing each group have median tumor volumes of ˜125 mm³ or ˜55 mm³ forthe Evans Blue dye assay.

To formulate compounds of the invention for dosing, the appropriateamount of compound is dissolved in 5% dextrose in water (D5W; AbbottLaboratories, North Chicago, Ill., USA). Vehicle-treated animals aredosed with D5W.

To conduct the Evans Blue dye assay, tumor-bearing animals are dosedwith vehicle or test article at 0 hr, and then i.v. injected with 100 IAof a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA)solution in 0.9% NaCl at +1 hr. Tumors are excised at +4 hr, weighed andthe tissue disassociated by incubation in 50 μL 1 N KOH at 60° C. for 16hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325 μLacetone are added, and the samples vigorously vortexed and thenmicrocentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant is then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that have not been injected with dye aresubtracted as background. OD₆₂₀ values are then normalized for tumorweight and dye uptake is calculated relative to vehicle-treated tumors.

To examine the vascular disrupting activity of a compound of theinvention, the Evans Blue dye assay is employed as a measurement oftumor blood volume (Graff et al., Eur J Cancer 36:1433-1440, 2000).Evans Blue dye makes a complex with serum albumin by electrostaticinteraction between the sulphonic acid group of the dye and the terminalcationic nitrogens of the lysine residues in albumin. The dye leaves thecirculation very slowly, principally by diffusion into extravasculartissues while still bound to albumin. Albumin-dye complex taken up bytumors is located in the extracellular space of non-necrotic tissue, andintracellular uptake and uptake in necrotic regions is negligible. Theamount of dye present in a tumor is a measurement of the tumor bloodvolume and microvessel permeability. Compounds of the invention areexpected to result in substantially decreased tumor dye uptake relativeto vehicle-treated animals. Such a decrease in dye penetration into thetumor is consistent with there being a loss of blood flow to tumors dueto blockage of tumor vasculature, consistent with a vascular disruptingmechanism of action.

Example 5 Inhibition of HUVEC Cell Migration

To examine if the compounds of the invention affect endothelial cellfunction, an in vitro human umbilical vein endothelial cell (HUVEC)migration assay is performed in the presence of a compound of theinvention. HUVEC cells (passage number 4) are cultured on 12-well platesand time-lapse imaging is performed with the live cell imaging system onan inverted microscope supplied with 6-7% CO₂. The temperature is keptat 37° C. Images are taken every 30 minutes using the 2× objective forup to 106 hr or every 60 seconds using the 20× objective for 30 min.Confluent HUVEC cultures are scraped similarly to make a blank area,followed by culturing in HUVEC medium for 15 hr without treatment. Themigration areas, which are imaged as time-lapse sequences for each well,are used as a basis to standardize/correct migration rates. Then,migration of cells under different treatments is imaged at the same timeto generate time-lapse image sequences for each well. Time-lapse moviesare further analyzed by measuring areas that are covered by migratingcells. During experiments, HUVEC cells are activated by the presence ofVEGF and basic FGF. Compounds of the invention (e.g. 100 nM and 1 μM)are expected to completely block migration of HUVEC cells to the blankarea, indicating that compounds of the invention possesses potentinhibitory effect on the migration of activated HUVEC cell in vitroinduced by VEGF and basic FGF.

It is also possible to track HUVEC behavior during above treatments. Itis expected that HUVEC cells will begin to shrink after 24 hr treatmentwith compounds of the invention.

Example 6 Enhanced VE-Cadherin Junctions of HUVEC cells

An immunofluoscence study is performed by using anti-VE-cadherinantibodies to examine VE-cadherin junctions between HUVEC cells. HUVECcells are treated with DMSO or a compound of the invention (e.g. 10, 100and 1000 nM) for 24 hrs and fixed for immunostaining DMSO concentrationis 1:100 for all treatments. To boost the immunofluorescence signal,cells are stained with a mixture of 2 polyclonal anti-human VE-cadherinAbs followed by staining with a mixture of fluorescent secondaryantibodies. It is expected that with compounds of the invention,VE-cadherin staining will be extremely strong in cell-cell junctionregions, but not the non-contacted regions compared to that in DMSOtreated cultures. Compounds of the invention are expected to enhance theassembly of cell-cell junctions of activated human endothelial cells,likely through induction of the accumulation of VE-cadherin molecules atthe junctions. This effect could result in limited motility of the cellsand reducing permeability of the endothelium, thus contributing to thecell migration inhibition and the potential anti-angiogenesis effect ofcompounds of the invention.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by the following structural formula:

a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R₁is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆,—O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)OH, —C(O)NHR₈, —C(O)SH,—S(O)OH, —S(O)₂OH, —S(O)NHR₈, —S(O)₂NHR₈, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;R₅ is an optionally substituted heteroaryl; R₆ and R₂₅, for eachoccurrence, are independently an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; R₇ and R₈, for each occurrence, are, independently, —H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted heteroaryl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedheteroaryl, or an optionally substituted heteraralkyl; or R₁₀ and R₁₁,taken together with the nitrogen to which they are attached, form anoptionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₂₆ is a lower alkyl; n is 0 or an integer from 1 to 4; x is1; n+x is less than or equal to 4; p, for each occurrence, is,independently, 0, 1 or 2; and m, for each occurrence, is independently,1, 2, 3, or 4; provided that, if R₅ is benzothiazolyl, R₂₅ and R₆ eachare not alkoxy.
 2. The compound of claim 1, wherein R₅ is represented bythe following structural formula:

wherein: R₃₃ is —H, a halo, lower alkyl, a lower alkoxy, a lowerhaloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, alower alkyl, or a lower alkylcarbonyl; and ring B and Ring C areoptionally substituted with one or more substituents.
 3. The compound ofclaim 1, wherein R₅ is an optionally substituted heteroaryl, in whichthe heteroaryl is selected from the group consisting of pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl,benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl,tetrazinyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,tetrahydroindolyl, azaindolyl, quinazolinyl, purinyl,pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl.
 4. The compound of claim 1represented by the following structural formula:

or tautomer, or a pharmaceutically acceptable salt thereof, wherein:X₁₀₁ is O, S, or NR₁₀₂; X₁₀₂ is CR₁₀₄ or N; Y, for each occurrence, isindependently N or CR₁₀₃; Y₁₀₁ is N or CR₁₀₅; Y₁₀₂ is N, C or CR₁₀₆; R₁is OH, SH, or NHR₇; R₆ is —H, —OH, —SH, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanidino a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₁₀₂ is —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R₇,—(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇,—S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; R₁₀₃ and R₁₀₄ are, independently, —H,—OH, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino,a haloalkyl, a heteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or R₁₀₃ and R₁₀₄ taken together withthe carbon atoms to which they are attached form an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heterocyclyl, or an optionally substituted heteroaryl; R₁₀₅is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁ or —NR₇C(NR₈)NR₁₀R₁₁; and R₁₀₆, foreach occurrence, is independently —H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.
 5. A process for making a pharmaceutical composition,comprising a compound of claim 1 and a pharmaceutically acceptablecarrier, which comprises mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 6. The compound of claim 1, whereinthe compound is represented by the following structural formula:

or tautomer, or a pharmaceutically acceptable salt thereof, wherein:X₁₀₃ is CR₁₀₄ or N; R₆ is —H, —OH, —SH, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₁₀₂ is —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C_(m)(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or—S(O)_(p)NR₁₀R₁₁; R₁₀₃ and R₁₀₄ are, independently, —H, —OH, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino,a haloalkyl, a heteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or R₁₀₃ and R₁₀₄ taken together withthe carbon atoms to which they are attached form an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heterocyclyl, or an optionally substituted heteroaryl; R₁₀₅is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; R₂₆ is a C1-C6alkyl; p, for each occurrence, is, independently, 1 or 2; and m, foreach occurrence, is independently, 1, 2, 3, or
 4. 7. The compound ofclaim 6, wherein R₆ is selected from the group consisting of —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy; R₁₀₂ is selected from the group consisting of —H, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂; and R₁₀₅ is selected from the group consisting of —H, —OH,methoxy, and ethoxy.
 8. The compound of claim 7, wherein X₁₀₃ is CR₁₀₄,and R₁₀₃ and R₁₀₄ are, independently, selected from the group consistingof —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,propoxy, and cyclopropoxy, or R₁₀₃ and R₁₀₄, taken together with thecarbon atoms to which they are attached, form a C₅-C₈ cycloalkenyl or aC₅-C₈ aryl.
 9. The compound of claim 1, wherein the compound isrepresented by the following structural formula:

wherein: R₂₅ is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, —OH,—SH, —NHR₇, —(CH₂)_(k)OH, —(CH₂)_(k)SH, —(CH₂)_(k)NR₇H, —OCH₃, —SCH₃,—NHCH₃, —OCH₂CH₂OH, —OCH₂CH₂SH, —OCH₂CH₂NR₇H, —SCH₂CH₂OH, —SCH₂CH₂SH,—SCH₂CH₂NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇,—SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇,—SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)R₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇; k is 1, 2, 3, or 4; and n is zero or an integer from 1to
 3. 10. The compound of claim 9, wherein the compound is representedby the following structural formula:

wherein R₆ is an optionally substituted alkyl or cycloalkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl,cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl,alkoxy, haloalkoxy, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, C(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,—C(O)NR₁₀R₁₁, —C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇,—C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, or —S(O)_(p)R₇.
 11. The compound of claim 10, wherein:R₁ is —SH or —OH; R₃ and R₂₅ are —OH; and R₆ is a C1-C6 alkyl, a C3-C6cycloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl,or —NR₁₀R₁₁.
 12. The compounds of claim 1, represented by the followingformulas: